Fifty years in search of selective antiviral drugs

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Perspective

Fifty years in search of selective antiviral drugs Erik De Clercq J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00175 • Publication Date (Web): 02 Apr 2019 Downloaded from http://pubs.acs.org on April 3, 2019

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Journal of Medicinal Chemistry

1

Fifty years in search of selective antiviral drugs

Erik De Clercq* KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium

______________ *Tel + 32 16 37 90 20 E-mail address: [email protected]

ABSTRACT Fifty years of research (1968-2018) towards the identification of selective antiviral drugs have been primarily focused on antiviral compounds active against DNA viruses (HSV, VZV, CMV, HBV) and retroviruses (HIV). For the treatment of HSV infections the aminoacyl esters of acyclovir were designed, and valacyclovir became the successor of acyclovir in the treatment of HSV and VZV infections. BVDU (Brivudin) still stands out as the most potent among the marketed compounds for the treatment of VZV infections (i.e. herpes zoster). In the treatment of HIV infections ten tenofovir-based drug combinations have been marketed, and tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) have also proved effective in the treatment of HBV infections. As a spin-off of our anti-HIV research, a CXCR4 antagonist, AMD-3100 was found to be therapeutically useful as a stem cell mobilizer, and has since 10 years been approved for the treatment of some hematological malignancies.

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2

Introduction In looking back at my scientific career now spanning 50 years in search of selective antiviral agents, I want to recount where my scientific research has, in some instances, yielded a successful outcome and in other cases, it did not, thereby illustrating that my scientific career, as life in general, was a mix of successes alternating with failures. In the framework of a “Perspective” article, I have not merely recounted the crucial events but also provided critical reflections, thus providing guidance for future developments. After I had started to work in the Laboratory (Rega Institute for Medical Research) of Prof. Piet De Somer in 1964, the real start of my scientific career could be situated in 1968, when on 4 September, I flew together with my wife Lili, whom I had just married on 31 August, to Palo Alto, via London, Los Angeles and San Francisco, the last segment by helicopter. I had obtained an Eli Lilly fellowship that would allow me to stay at Stanford University for one year in the Laboratory of Thomas C. Merigan. After a few months, both Lili and I were so much enchanted by our life in the Bay Area that I continued to stay for another year, this time with the aid of a Damon Runyon fellowship. In November 1970 we returned home with mixed feelings, partly depressed for having to leave Stanford behind, but partly looking forward to resuming the work with my boss, Prof. De Somer. He had, in the meantime, broken his ties with the Company RIT in Genval, which he had founded, and, instead, had embarked on a new career as the first president (Rector) of the new autonomous Flemish University of Leuven, while retaining his position as Director of the Rega Institute. Little I knew at the end of the 1970s that I would stay there for my whole life.


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3

Interferon inducers The discovery of interferon in 1957 by Isaacs and Lindenmann1 as an antiviral substance stimulated worldwide efforts on (i) how to actively (i.e. endogenously) induce this substance, and (ii) how to produce it (exogenously). When starting to work, as a young MD, in the Laboratory of Prof. Piet De Somer, I followed the first approach, and this swiftly led to the identification of some synthetic polyanions, i.e. polyacrylic acid, as inducers of interferon.2, 3 That synthetic polyanions such as pyran copolymer, were able to induce interferon, had already been shown by Tom Merigan4, 5, but what had really galvanized the field of interferon induction, was the observation of Maurice Hilleman and his team at Merck that interferon could be induced by double-stranded (ds)RNAs, including poly (I).poly(C), four articles being published in PNAS in 19676-9 and one in 1968.10 When I left Leuven for Stanford in September 1968, high expectations were vested on interferon inducers, especially dsRNAs such as poly(I).poly(C), and thus my research at Stanford was primarily focused on the mechanism, and structured requirements, of induction of interferon by dsRNAs. This led, within a few months, to two papers in Nature11, 12, and one in Science.13 The latter paper, co-authored by my first foreign collaborator, Fritz Eckstein, reported the thiophosphatesubstituted polyribonucleotides, i.e. poly (As-Us), as inducers of interferon. This finding was patented and licensed by Stanford University to the Company Wyeth, who abandoned the further pursuit of poly (As-Us) a few years later. Back in Leuven, I continued the study of the mechanism of interferon induction by poly(I).poly(C)14, and the structural requirements of dsRNAs to induce interferon15, and with Bill Carter, I reviewed the role of dsRNA during the virus infection process.16 While arduous attempts to increase the interferon inducing potency and/or safety of poly(I).poly(C) by a variety of chemical modifications did not yield the expected results, the compound proved to be of paramount importance in the cloning and expression of human ß-interferon.17, 18 This work was based on a close collaboration between three laboratories, that of Walter Fiers (University of Ghent), that of Jean Content (Pasteur Institute in Brussels) and mine in Leuven. The human ß-



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4 interferon, thus produced exogenously, found its primary application beyond the antiviral area that is in the treatment of multiple sclerosis (MS).

Suramin Just before my return from Stanford to Leuven, I was fascinated by two consecutive papers in Nature reporting the discovery of the reverse transcriptase (RT).19, 20 Upon my return in Leuven, I verified on my own whether murine (Moloney) leukemia virus really harbored such enzyme, and so it did, and the existence of the RT was confirmed in several other laboratories, including that of Robert C. (“Bob”) Gallo. With the RT assay system at hand, I evaluated a series of compounds as potential RT inhibitors. Sol Spiegelman had published in PNAS on the purported role of the RT in all sorts of cancers, and when in 1975 I found the polysulfonate suramin (Fig. 1) to be exquisitely inhibitory to the (murine) RT, I instantly determined to measure its propensity to block leukemia in mice. To my great disillusion, it did not. This made me to disbelieve in the role of RT in cancer. When several years later (1978), Bob Gallo visited us at the Rega Institute, and I informed him about my observations with suramin, he told me I should publish these findings in his journal, Cancer Letters, and so I finally did.21 This was 2 years before AIDS (Acquired Immune Deficiency Syndrome) was identified, and 4 years before HIV, then called HTLV-III (human T-cell lymphotropic virus type 3) or LAV (lymphadenopathy-associated virus), was suggested to be the possible cause of the disease.

Comment When suramin was first evaluated for its activity against HTLV-III, it was assumed to act as an RT inhibitor. It was later ascertained that this was only part of its mode of action. Being a polyanionic substance it also proved inhibitory to the virus adsorption to the cells.


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5

Suramin

Fig. 1: Suramin I was pleasantly surprised that in 1984, based on my original paper in Cancer Letters, Gallo and his colleagues at the NCI (National Cancer Institute) had found suramin to be active against the replication of HTLV-III in vitro22, and in vivo, in AIDS patients.23 However, suramin, that had been marketed for the treatment of African trypanosomiasis (“sleeping sickness”) since 1920, was considered to be too toxic for therapeutic use in the treatment of AIDS, especially because at the NCI they had in the meantime come across a compound, azidothymidine (AZT)24, that was more active against HTLV-III, and apparently less toxic than suramin. Ironically, I had already evaluated AZT for its antiviral activity at the end of the 1970s25, but retroviruses at that time had not been included in our assay systems. Furman would then further ascertain that RT was the final target for the mode of action of AZT26, and in 1987, AZT (Retrovir®) would become the first anti-HIV drug formally approved by the US Food and Drug Administration (FDA).

DHPA



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6 In 1976, a few months after we had met for the first time at the Max Planck Institut für Biophysikalische Chemie in Göttingen, Antonín Holý sent me three compounds for antiviral evaluation. One of the three compounds, S-9-(2,3-Dihydroxypropyl)adenine (DHPA) (Fig. 2) turned out to be antivirally active. We published this finding in Science.27 We thought DHPA was the first acyclic nucleoside analogue ever shown to be antivirally active, until we learned that just a few months earlier that

year

Schaeffer

et

al.28

had

published

on

the

activity

of

acyclovir

(9-(2-

hydroxyethoxymethyl)guanine) “against viruses of the herpes group”. In fact, the selective anti-

herpes activity of acydovir, due to a specific recognition by the viral thymidine kinase had already been introduced by Gertrude (“Trudy”) Elion in the 1977 December PNAS issue.29 In contrast with acyclovir, DHPA exhibited broad-spectrum antiviral activity against both DNA and RNA viruses, which, as we later demonstrated, was due to a specific interaction with the Sadenosylhomocysteine (SAH) hydrolase.30 Various adenosine analogues, whether acyclic or cabocyclic, were found to display broad-spectrum antiviral activity31, due to a specific interaction with the SAH hydrolase, which was first recognized by John Montgomery as a pharmacological target in 1982.32 DHPA was marketed in the former Czechoslovakia by Lachema Company as Duviragel® for the topical treatment of herpes labialis (“cold sores”) due to herpes simplex virus (HSV) infection; it was later abandoned.

Comment DHPA was brought onto the market despite the paucity of clinical data in this regard. More convincing data were generated for the potential of BVDU in the topical treatment of herpes labialis, but, ultimately, the only compound licensed for clinical use in the topical treatment of HSV infections was acyclovir (Zovirax®).


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7 NH2 N

N

N N

OH OH DHPA

Fig. 2: DHPA

BVDU

Within a year following acyclovir, BVDU [(E)-5-(2-Bromovinyl)-2'-deoxyuridine] was described as a specific anti-herpesvirus agent.33 Among the herpesviruses, particularly HSV-1 (herpes simplex virus type I) and VZV (varicella-zoster virus) proved highly sensitive to BVDU, as the thymidine kinase encoded by these viruses efficiently phosphorylated BVDU in the virus-infected cells, the ultimate target for the antiviral action being the viral DNA polymerase.34 BVDU entered the clinic on a compassionate basis in 1980, for the treatment of VZV infections (i.e. herpes zoster).35 In cell culture, it proved about 1000-fold more potent an inhibitor of VZV replication than acyclovir, and anecdotal evidence also indicated that BVDU was more effective than acyclovir in the topical treatment of HSV1 infections (i.e. herpes labialis and herpetic keratitis). Yet, unlike acyclovir, BVDU was never commercialized for these indications. Instead, it was widely marketed, first in East Germany (as Helpin), and later in the whole of Germany (as Zostex®), and other countries [as Brivirac® (Italy), Zerpex® (Belgium), etc.] (Fig. 3), for the treatment of VZV infections (i.e. herpes zoster). The commercial package mentions that BVDU (also known as brivudin) should not be given concomitantly with anticancer agents: this restriction only concerns 5-fluorouracil (derivatives), since,



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8 in Japan, the concomitant use of fluorouracil (derivatives) and sorivudine (BV-araU, which is not identical but structurally related to BVDU) was found to lead to some casualties, due to an increased toxicity of 5-fluorouracil. However, for BVDU no such casualties have ever been noted or reported.

O

O

Br

HN

HN O

Br

O

N

P

O

P

P

O

N O

HO

OH

OH

BVDU

BVDU 5'-triphosphate

Fig. 3: BVDU and BVDU 5’-triphosphate

Comment Why was BVDU not marketed for herpes zoster in the US, and not marketed for the treatment of HSV-1 infections worldwide? The main reason is that acyclovir (and valcyclovir) had monopolized the market for this indication, which added up to the paucity of comparative clinical data for HSV infections, and the inactivity of BVDU against HSV-2.

Aminoacyl esters of acyclovir

Acyclovir was the first specific antiviral compound ever introduced in the medical practice for the systemic treatment of (herpes) viral infections [actually, vidarabine (ara-A) was the first to be introduced in the systemic treatment of VZV infections36, but this compound was not considered as


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9 “specifically” antiviral]. The problem with acyclovir, however, was that, first, it was not sufficiently bioavailable by the oral route, and, secondly, not highly soluble in aqueous medium (although more so than vidarabine). In attempts to overcome the second problem, aminoacyl (i.e. glycyl and alanyl) esters of acyclovir were developed.37 Glycyl acyclovir proved applicable as eye drops in the treatment of herpetic eye infections (i.e. keratitis)38, an advantage over acyclovir that had to be administered as an eye ointment. The most important advantage, however, was that one of aminoacyl esters, particularly, the valine ester, valacyclovir, showed a much better oral bioavailability than the parent compound.39, 40 Valacyclovir would finally replace acyclovir, when the latter turned out to be generic (in 1995), and be marketed as Valtrex® (US) or Zelitrex® (EU) (Fig. 4), for the oral treatment of both HSV and VZV infections.

O N

O NH

N

O N H 2N

O

N

NH

NH2

O

P

P

P

Valacyclovir (VACV)

O

N O

ACV triphosphate

Fig. 4: Valacyclovir (VACV) and ACV triphosphate

Comment


N

NH2


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10 When acyclovir was launched, its main benefit in comparison with the then known antivirals was that it was considered to be the first selective antiviral agent active against HSV infection28, based on its specific recognition (and phosphorylation) by the HSV-encoded thymidine kinase.29

Acyclic nucleoside phosphonates (ANPs): (S)-HPMPA, PMEA (Adefovir), (S)-HPMPC (Cidofovir)

The prototype of the acyclic nucleoside phosphonates (ANPs) was [(S)-9-(3-hydroxy-2phosphonomethoxypropyl)adenine] (Fig. 5). It was first described in 1986.41 It showed selective activity against a broad range of DNA viruses, including herpes-, papilloma-, polyoma-, adeno-, hepadna- and poxviruses. Although (S)-HPMPA was not commercialized for clinical use in humans, it paved the way to the development of tenofovir [(R)-PMPA], which in its prodrug form, tenofovir disoproxil fumarate (TDF), and, later on, TAF (tenofovir alafenamide) would become the key compound for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. NH2 N

N

O

HO P

N N

O

HO OH

(S)-HPMPA

Fig. 5: (S)-HPMPA or (S)-9-(3-Hydroxy-2-phosphonomethoxypropyl)adenine Concomitantly with (S)-HPMPA, PMEA [9-(2-phosphonomethoxyethyl)adenine] was described as an antiviral agent specifically active against retroviruses.41 PMEA (adefovir) in its prodrug form, adefovir dipivoxil (Hepsera®) (Fig. 6) would be approved in 2002 by the US FDA, and marketed


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11 worldwide by Gilead Sciences, for the treatment of HBV infections. It was originally intended for clinical use in the treatment of HIV infections.

NH2

NH2

N

O

HO P

N

N

N

N

O

N

H2 C

N

(H3C)3C

O

O

O

O (H3C)3C

HO

PMEA

O

O P

H2 C

N

O

O

PMEA Dipivoxil NH2 N

N

O

HO P

N N

O

O P P

PMEA diphosphate

Fig. 6: PMEA, PMEA dipivoxil and PMEA diphosphate

In 1987, the pyrimidine counterpart of (S)-HPMPA, (S)-HPMPC [(S)-1-(3-hydroxy-2phosphonomethoxypropyl)cytosine] was described as a broad-spectrum anti-DNA virus agent with an activity profile similar to that of (S)-HPMPA.42 After Gilead acquired the licensing rights on the whole family of the ANPs in 1991, it took them only 5 years to launch (S)-HPMPC (cidofovir, Vistide®) (Fig. 7)



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12 in 1996, as the first ANP ever marketed by Gilead, for the parenteral treatment of human cytomegalovirus (CMV) retinitis in AIDS patients. CMV retinitis was a severe infection of the eye (retina) leading to blindness that is no longer observed nowadays because of the efficient chemotherapy that in the meantime has been developed to treat HIV infection (AIDS). Cidofovir has been sublicensed by Gilead to Upjohn, then Pharmacia, and later to Pfizer. It has been used, off label, on a compassionate basis for the treatment of various DNA virus infections, including herpes-, adeno-, papilloma-, polyoma- and poxvirus infections [representative examples of the human papilloma virus (HPV) infections being laryngeal papillomatosis and genital warts, and of the poxvirus infections being monkeypox, orf and molluscum contagiosum].

Comment When the choice had to be made for clinical development of (S)-HPMPA versus (S)-HPMPC, the latter was chosen because it had a more favorable safety profile in the initial toxicity studies. This, in turn, explains why (S)-HPMPC was later licensed for clinical use and why little or no attention was reserved for the possible clinical use of (S)-HPMPA in the treatment of DNA virus infections.


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13

NH2

NH2

N

O

HO P

O

N

N

O

HO P

O

O

N

O

O

HO P

OH

P

OH

(S)-HPMPC (Cidofovir)

(S)-HPMPC diphosphate

Fig. 7: (S)-HPMPC (Cidofovir and (S)-HPMPC diphosphate

Stavudine

The first antiretroviral drug ever approved in the US by the FDA was AZT (azidothymidine, zidovudine) in 1987. AZT is the prototype of the nucleoside reverse transcriptase (RT) inhibitors (NRTIs), which following their intracellular phosphorylation to the triphosphorylated metabolite, act, as chain terminators, of their target enzyme, RT. Following AZT, several other 2’,3’-dideoxynucleoside analogues were found at the NCI by Mitsuya and Broder43 to inhibit the replication of HTLV-III. Two of these compounds, 2’,3’-dideoxyinosine (ddI, didanosine) and 2’,3’-dideoxycytidine (ddC, zalcitabine) would be commercialized by Bristol-Myers (now Bristol-Myers Squibb) for the treatment of HIV infections (zalcitabine is no longer used in medical practice). The fourth NRTI ever approved by the US



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14 FDA as an anti-HIV drug, 2',3'-dideoxy-2’,3’-didehydrothymidine (d4T), was first described in our laboratory at the Rega Institute in Leuven44, and, independently but several months later confirmed by Lin et al.45 at Yale University and Hamamoto et al.46 in Tokyo. The compound, meanwhile known as stavudine, was commercialized by Bristol-Myers Squibb under the trade name Zerit® (Fig. 8). It would gain wide acceptance all over the world as an anti-HIV drug, until it was superseded by the acyclic nucleoside phosphonate, tenofovir (see infra).

O

O

HN O

HN

N

O P

O

P

P

O

N O

HO

d4T Stavudine

d4T 5'-triphosphate

Fig. 8: d4T Stavudine and d4T 5‘-triphosphate

Comment The discovery of AZT as inhibitor of HTLV-III/LAV replication24 generated worldwide interest in many chemical laboratories, including our own, where it prompted Piet Herdewijn to synthesize several related thymidine analogues, including d4T. These compounds were sent for evaluation against HTLVIII/LAV to Sam Broder’s Lab, which, using the ATH8 cell line, did not detect meaningful specificity in


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15 their activity against the virus (first few months of 1986). When Masanori Baba (in the second half of 1986) evaluated d4T for its activity against the AIDS virus (then called HIV), using the MT-4 cell line, he found remarkable activity.44

NNRTIs

The original discovery of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) dates from 1989-1990 when I described two seemingly unrelated classes of compounds, (i) the HEPT [1-[(2hydroxyethoxy)methyl]-6-phenylthiothymine]

derivatives47,

48,

and

(ii)

the

TIBO

[tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(IH)-one] derivatives49, 50, which appeared to act as RT inhibitors by a mechanism (allosteric inhibition) that was totally different from that of the classical NRTIs. 51, 52 The HEPT and TIBO derivatives could be regarded as the first NNRTIs , which, although they were themselves finally not marketed, they gave rise to five compounds which were eventually commercialized for the treatment of HIV infections: nevirapine (Viramune®), delavirdine (Rescriptor®, later abandoned), efavirenz (Stocrin®, Sustiva®), etravirine (Intelence®) and rilpivirine (Edurant®). Of the HEPT derivatives, emivirine (Coactinon®) (Fig. 9) proceeded to phase III clinical trials53, when its further development was halted, mainly because of a too competitive market. The cumbersome chemical synthesis of the TIBO derivatives hampered their further clinical development, but, instead, gave rise to the DAPYs that ultimately yielded etravirine, rilpivirine (Fig. 10) [which has become part of the cocktails with TDF and TAF (see infra), and dapivirine, which has been pursued in a vaginal ring for HIV prevention in women.54, 55



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16 O HN O

CH3

O HN

N

S

HO

O

CH3 N

HO

O

O

HEPT

Emivirine

Fig. 9: HEPT and Emivirine

N

S

N

HN N

N

HN

N

NH N

TIBO

Rilpivirine

Fig. 10: TIBO and Rilpivirine


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17 All NNRTIs, while structurally unrelated, behave conformationally as a similar structure that could be described as a “butterfly” or “horseshoe”, and fits snugly within the non-nucleoside binding “pocket” site within the HIV-I reverse transcriptase located at some distance (10-15 Å) from the catalytic site.56, 57, 58 The conformational similarity between the HEPT derivatives (i.e. emivirine) and TIBO derivatives (i.e. tivirapine) had originally been suggested long before it was elaborated for all the other NNRTIs.59

Comment The first NNRTIs ever discovered were the HEPT47, 48 and TIBO49 derivatives. From the HEPT analogues, emivirine was derived, that eventually was not marketed, and thus could be considered a failure in drug development. The TIBOs, however, through a process of judicious medicinal chemistry led by the late Dr. Paul Janssen, culminated in the identification of rilpivirine as an almost ideal anti-HIV drug.60 The compound was marketed as such and in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine as Complera® (US)/Eviplera® (EU), and in combination with tenofovir alafenamide (TAF) and emtricitabine as Odefsey®, for the treatment of HIV infections.

Bicyclams, plerixafor

In our search for new and more potent and selective anti-HIV agents, we discovered in 1992, totally unexpectedly, a totally new class of compounds, the bicyclams, as an impurity present in a commercial cyclam preparation obtained from the company Lancaster; the impurity itself could not be resynthesized, so at Johnson Matthey a program was started to synthesize bicyclams tethered by an aliphatic (propyl) linker. The compound thus obtained, JM2763, had reasonable anti-HIV activity, as published in a PNAS article sponsored by the Nobel laureate, Max Perutz.61



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18 When, however, the aliphatic bridge between the two cyclam rings was replaced by a phenylbis(methylene) linker as in JM3100, the anti-HIV potency increased by 100-fold62 [effective concentration being 1-10 nM; selectivity index: 100,000]. The target of action was initially thought to be the viral envelope glycoprotein gp120. It appeared only to be the indirect target. The direct target of action turned out to be the co-receptor CXCR4 used by T-lymphotropic HIV strains to enter the cells.63, 64 CXCR4 normally functions as the receptor for the chemokine SDF-1 (stromal derived factor -1) (now called CXCL12) and is involved in various physiopathological processes, one being the “homing” of hematopoietic stem cells (HSCs) to the bone marrow. When initial (phase I) clinical trials were undertaken with AMD3100 (new name for JM3100 after AnorMED had been founded) (Fig. 11) as a prelude to its development as a candidate anti-HIV drug, an unexpected side effect, an increase in the white blood cell (WBC) counts was observed.65 On closer inspection, these WBCs appeared to be CD34+ HSCs. 66, 67 And, thus AMD3100 could be regarded as a stem cell mobilizer. The AMD3100 saga has been the subject of consecutive review articles.68-72 AMD3100 has since December 2008 been formally approved by the US FDA for autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) or multiple myeloma (MM). The compound is also known as plerixafor and marketed as Mozobil®. AnorMED has in the meantime been taken over by Genzyme, which, in turn, has been incorporated into Sanofi. As a stem cell mobilizer, AMD3100 may be pursued for various other applications than it was originally intended for.72

Comment The discovery of AMD3100 as a stem cell mobilizer should be viewed as the result of a few serendipitous events: it started with the identification of an impurity (“bicyclams”) in a monocyclam preparation, which appeared to be quite active against HIV, and, upon further clinical studies, the


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19 compound appeared to cause an increase in the WBC counts, due to the mobilization of the hematopoietic stem cells from the bone marrow.

NH

N

NH

HN

N

HN

NH

HN

Bicyclam AMD3100

Fig. 11: Bicyclam AMD3100, plerixafor

(R)-PMPA (tenofovir), tenofovir disoproxil fumarate (TDF, Viread®)

In 1993, we described two closely related derivatives of (S)-HPMPA called (R)-PMPA [(R)-9-(2phosphonomethoxypropyl)adenine]

and

(R)-PMPDAP

[(R)-9-(2-phosphonomethoxypropyl-2,6-

diaminopurine].73 The DAP (2,6-diaminopurine) derivative was actually more potent than its adenine (6-aminopurine) counterpart, but the latter was chosen by Gilead Sciences for further clinical development. It was named tenofovir, and in its prodrug form, tenofovir disoproxil fumarate (TDF) (Fig. 12) became worldwide one of the best known antiretroviral drugs for the treatment of HIV infections. [Disoproxil stands for bis (isopropyloxycarbonyloxymethyl), the bis ester of (R)-PMPA that had been designed to ensure the oral bioavailability of (R)-PMPA74, 75].

Comment



Page 20 of 50

20 (R)-PMPA, rather than (R)-PMDAP, was chosen for clinical development, for the simple reason that the adenine was a natural base, whereas the 2,6-diaminopurine (DAP) was not, and it was felt that, if nature had selected adenine over DAP, there must have been a good reason for it (i.e. mutagenicity).

In retrospect, a decisive observation was made in 1995 by Tsai and his colleagues76, who demonstrated that (R)-PMPA could completely prevent the infection of simian immunodeficiency virus (SIV) in monkeys, whereas AZT, tested in parallel, only slightly did so. At the time this paper was published in Science (17 November 1995), it could hardly be foreseen that 17 years later, on 16 July 2012, exactly the same day that Antonín Holý died, the US FDA would approve, as the first chemical ever, Truvada®, or the combination of TDF with emtricitabine, for the prophylaxis of HIV infections. NH2 NH2

N

N

N

N

N

N OH

(H3C)2

O P

O

OH

(H3C)2

O

CH2 O

O

CH2

O

O

CH2

CH3

HOOC CH

O

O

CH2

N

N O P

CH

O

COOH

O CH3

(R)-PMPA (Tenofovir)

Tenofovir disoproxil fumarate (TDF)

NH2 N

N

N

N OH

O P

O

O P P

CH3

(R)-PMPA diphosphate

Fig. 12: (R)-PMPA (Tenofovir), Tenofovir disoproxil fumarate (TDF), (R)-PMPA diphosphate


Page 21 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


21 Comment The observations of Tsai et al.76 laid the basis for the use of the combination of TDF and emtricitabine in the pre-exposure prophylaxis (PrEP) of HIV infections, as formally approved in 2012 in the US, and 4 years later in the EU.

Tenofovir disoproxil fumarate (TDF) was approved by the US FDA in 2001 for the treatment of HIV infections and in 2008 for the treatment of HBV infections. After it had been approved (Fig. 13), for the prevention of HIV infections in the US in 2012, it was also approved on 22 August 2016, in the EU for what is now commonly referred to as PrEP (pre-exposure prophylaxis) of HIV infections. Among African women, tenofovir-based prophylaxis did not appear to significantly reduce the rate of HIV infections [FEM-PrEP study77; VOICE study78], but the negative outcome of these studies could be attributed to the low drug adherence.

NH2 F N

O

HO

N

S

O

(-)FTC (Emtricitabine, Emtriva®)

Fig. 13: Tenofovir disoproxil fumarate (TDF)(Fig.12) and (-)FTC (Emtricitabine)



Page 22 of 50

22

TDF as cornerstone of anti-HIV drug combinations

After the combination of TDF and emtricitabine had been approved by the US FDA in 2004 for the treatment of HIV infections, followed in 2006 Atripla® (Fig. 14) (combination of TDF with emtricitabine and efavirenz), in 2011 Complera® (US), Eviplera® (EU) (combination of TDF with emtricitabine and rilpivirine) (Fig. 15) and in 2012 the quadruple drug combination of TDF, emtricitabine, elvitegravir and cobicistat (Stribild®) (Fig. 16), all for the treatment of HIV infections.

Cl

CF3 O

N H

O

Efavirenz

Fig. 14: Tenofovir disoproxil fumarate (TDF)(Fig. 12), (-)FTC (Emtricitabine)(Fig.13), and Efavirenz

N

N

HN

N

NH

N

Rilpivirine


Page 23 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


23

Fig. 15: Tenofovir disoproxil fumarate (TDF)(Fig. 12), (-)FTC (Emtricitabine)(Fig. 13), and Rilpivirine



Page 24 of 50

24

OH H

O

O

N

N O

OH F

O

O

O H N

N

S N

N H

N H O

O

S

N

Cl

Elvitegravir

Cobicistat

Fig. 16: Tenofovir disoproxil fumarate (TDF)(Fig. 12), (-)FTC (Emtricitabine)(Fig. 13), Elvitegravir, and Cobicistat


Page 25 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


25

Tenofovir alafenamide (TAF): successor of TDF in anti-HIV combinations

Provisions were taken from 2015 to replace tenofovir disoproxil by another prodrug of tenofovir, tenofovir alafenamide (TAF), which by Gilead scientists (Lee et al.)79 had been shown to be preferentially taken up by the lymphatic tissue, and, as shown by Birkus et al.80, by liver cells as well. Thus, the marketed drug for TDF was replaced by Vemlidy® (Fig. 17) in 2016 for the treatment of both HIV and HBV infections; it was approved in the US on 10 November 2016, in Japan on 19 December 2016 and in the EU on 11 January 2017. The quad tablet that combined elvitegravir, cobicistat, emtricitabine and TDF (Fig. 16) was replaced by Genvoya (Fig. 18) (combination of TAF, emtricitabine, elvitegravir and cobicistat) for the treatment of HIV infections; it was approved in the US on 5 November 2015 and in the EU on 23 November 2015. Then followed approval of Descovy® (combination of TAF with emtricitabine) (Fig. 19) on 4 April 2016 (US) and 25 April 2016 (EU), Odefsey® (combination of TAF, emtricitabine and rilpivirine) (Fig. 20) on 1 March 2016 (US) and 29 April 2016 (EU), Biktarvy® (combination of TAF, emtricitabine and bictegravir) (Fig. 21) on 7 February 2018 (US) and 27 April 2018 (EU), and Symtuza® (combination of TAF, emtricitabine, darunavir and cobicistat) (Fig. 22) on 26 September 2017 (EU) and 17 July 2018 (US), all for the treatment of HIV infections. Whether the combination of TAF with emtricitabine (Fig. 19), akin to the combination of TDF with emtricitabine (Fig. 13), or any of the other TAF-based drug regimens might ever replace the drug based on the combination of TDF with emtricitabine (Fig. 13) in the prophylaxis (PrEP) of HIV infections needs to be further explored.



Page 26 of 50

26 NH2 N

N

O

O

N

P

O

N

HN CH3

O CH3 O

Tenofovir alafenamide (TAF

Fig. 17: Tenofovir alafenamide (TAF)

Fig. 18: Tenofovir alafenamide (TAF)(Fig. 17), (-)FTC (Emtricitabine (Fig. 13), Elvitegravir (Fig. 16), and Cobicistat (Fig. 16)

Fig. 19: Tenofovir alafenamide (TAF)(Fig. 17), and (-)FTC (Emtricitabine)(Fig. 13)


Page 27 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


27

Fig 20: Tenofovir alafenamide (TAF)(Fig. 17), (-)FTC (Emtricitabine)(Fig. 13), and Rilpivirine (Fig. 15)

O

F

H

H O

N

N H

N F

O H

O

F

OH

Bictegravir (BIC)

Fig. 21: Tenofovir alafenamide (TAF)(Fig. 17), (-)FTC (Emtricitabine)(Fig. 13), and Bictegravir (BIC)

NH2 OH H

H N

O O

N S

H

O

O

O

H

Ph O

Darunavir



Page 28 of 50

28 Fig. 22: Tenofovir alafenamide (TAF)(Fig. 17), (-)FTC (Emtricitabine)(Fig. 13), Darunavir, and Cobicistat (Fig. 16)

With the current TAF-based drug combinations, we now have at hand a series of anti-HIV therapeutics (i.e. see Fig. 18, 20, 21 and 22), that fulfill the requirements for the optimal treatment of HIV infections, a single oral pill per day, which combines efficiency with safety, tolerability and the quasi lack of resistance development.

Comment The use of drug combination therapy based on either TDF or TAF in the treatment of HIV infections is reminiscent of the strategy that has since half of a century been followed for the treatment of tuberculosis (TB), that is combination therapy of isoniazid, rifampicin and pyrazinamide (with or without ethambutol). The goals are the same: (i) to reduce the individual dosages so as to maximize tolerability, (ii) to stimulate synergism between compounds interacting at different molecular targets, and (iii) to minimize the risk for resistance development.


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29

Rabacfosadine

Among the first ANPs ever described for their antiviral properties also featured PMEG [9-(2phosphonomethoxyethylguanine].42 However, the compound was considered to be too cytotoxic for further development as a potential antiviral drug. Instead, John C. Martin and his colleagues at Gilead Sciences found it more active than (S)-HPMPA and PMEA in inhibiting P388 leukemia in mice.81 We then found a prodrug of PMEG, cPr-PMEDAP [9-(2-phosphonomethoxyethyl)-N6-cyclopropyl-2,6diaminopurine] to block choriocarcinoma in rats.82 Apparently, cPr-PMEDAP would be converted to PMEG through the same enzyme converting abacavir 5’-monophosphate to carbovir 5’monophosphate.83 When further equipped with a phosphonoamidate moiety to increase the efficiency of lymphoid cell loading, a pro-prodrug of PMEG was obtained, namely GS-9219 (diethyl N, N’-[({2-[2amino-6-(cyclopropylamino)-9H-purin-9-yl]ethoxy}methyl)phosphonoyl]di-L-alaninate).84

This

compound would later also be known as VDC-1101 and rabacfosadine. It was shown by Reiser et al.84 to be exquisitely effective in the treatment of non-Hodgkin’s lymphoma (NHL) in dogs, and after being sublicensed by Gilead Sciences to VetDC, it was (conditionally) approved in 2017 by the US FDA for the treatment of lymphoma in dogs. The compound is marketed as Tanovea® (Fig. 23) by VetDC. It acts as a pro-prodrug of PMEG, and its eventual active metabolite is the diphosphate of PMEG (PMEGpp), which inhibits DNA synthesis in direct competition with the natural substrate dGTP.85

Comment GS-9219 was originally pursued for its potential in the treatment of NHL in humans. The rationale behind it was its preferential activity against tumors of the lymphoid system. Veterinary use (in the treatment of NHL in dogs) has been given higher priority than its potential medical use.



Page 30 of 50

30

NH N

N H 2N

O NH O

N

N

O P

O

O N H O

GS-9219 Rabacfosadine

GS-9219

O NH N H 2N HO

N

N

N

N

HO

O P

NH

N

O P

O

N

O

HO

HO

cPr-PMEDAP

PMEG

O N

N

HO

NH N

NH2

O P

O

O P P

PMEG diphosphate

Fig. 23: GS-9219 (Rabacfosadine), cPr-PMEDAP, PMEG and PMEG diphosphate


NH2

Page 31 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


31

Bicyclic nucleoside analogues (BCNAs): Cf1743, FV100

The bicyclic nucleoside analogues [prototype Cf1743 (Cf standing for Cardiff)] were first described by McGuigan et al.86 They are called bicyclic because they contain a furan ring condensed with a pyrimidine ring mounted on a 2-deoxyribose. The unique feature of Cf1743 is that it is specifically active against VZV, and not any other viruses, not even HSV-1 (unlike BVDU), but against VZV, it is still the most potent inhibitor that has ever been discovered.87 Its mechanism of action has only partly been resolved. For its anti-VZV activity it strictly depends on the viral thymidine kinase (TK), as TK-negative mutants are not sensitive to the inhibitory activity of the compound.88 Unlike BVDU, it cannot be cleaved at its N-glycosidic linkage by (pyrimidine) phosphorylase(s), so that it would not interfere with the degradation of FU (5-fluorouracil), which - as has been shown for BVaraU – would otherwise increase the toxicity of FU (and its derivatives). FV-100 (FV standing for Fermavir), the 5’valine ester of Cf1743 (Fig. 24), has been designed to increase the oral bioavailability of Cf174389). FV100 has been the subject of a phase II clinical trial in patients with herpes zoster90; the promising results obtained in this trial suggested that follow-up studies were warranted, but these have, to the best of my knowledge, not been divulged or published (so far).

O O

N

N

O O HO

N

H C

H 2N

O

C

O O

N O

HC H 3C

CH3 OH

OH

Cf 1743

FV100

Fig. 24: Cf1743 and FV100 (5’-Valine ester of Cf1743)



Page 32 of 50

32

Comment FV100 suffers in its further development from the same problem that has also hampered the wide application of BVDU, that is that its activity is restricted to VZV (while BVDU also covers HSV-1), and for big pharmaceutical internationals this is often regarded as too small a market, certainly when the compound has to be given for a short period of time (i.e. herpes zoster) and cannot be extended to a larger patient population (HSV-1 and HSV-2 infections).


Page 33 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


33

ANPs that deserve further exploration

From the PMEG prodrug cPrPMEDAP, two prodrugs were developed, termed GS-9191 and GS9219, respectively, which could thus be regarded as “proprodrugs” of PMEG. GS-9219 (Fig. 23) has in the meantime been marketed for the treatment of non-Hodgkin’s lymphoma in dogs, whereas GS9191 (Fig. 25) was further pursued for its potential usefulness in the topical treatment of genital warts.91 How GS-9191 eventually fared, is at present unclear. A new class of ANPs, that of the O-DAPys, {6-[2-(phosphonomethoxy)alkoxy]-2,4-diamino pyrimidines, with (R)-HPMPO-DAPy, PMEO-DAPy and (R)-PMPO-DAPy (Fig. 25) as the prototypes, was introduced by Holý and his colleagues in 2002.92, 93 (R)-HPMPO-DAPy showed a similar spectrum of activity as cidofovir (and should have been further explored for its potential in the treatment of herpes, polyoma-, papilloma-, adeno- and poxvirus infections), whereas PMEO-DAPy and (R)PMPO-DAPy deserved further attention for their potential in the treatment of HIV and HBV infections.94 What makes the O-DAPys so attractive from a mechanistic viewpoint is that, being pyrimidine derivatives they behave as purine nucleotide mimetics in inhibiting the DNA polymerase (i.e. reverse transcriptase) reaction. Following an old tradition at the Institute of Organic Chemistry and Biochemistry (IOCB), Holý and his colleagues also synthesized the triazine counterpart of (S)-HPMPC, 5-aza-(S)-HPMPC.95,

96

Although 5-aza-(S)-HPMPC (Fig. 25) had some favorable pharmacological advantages over (S)HPMPC97, neither 5-aza-(S)-HPMPC nor its alkoxyalkyl prodrugs have – heretofore – been further pursued for their therapeutic potential.



Page 34 of 50

34 Comment Whether any of the new ANPs originating from Dr. Holý’s legacy will ever be developed in human or veterinary medicine will depend on a number of factors, including the specific advantages over the established ANPs and/or the new needs that may eventually emerge in the future.

NH N

N H 2N

N

N

O

O NH

P

O

O NH

O

O

GS-9191 NH2

N

NH2

P

NH2

O

OH

N

N

O

O

OH

NH2

NH2

N

N

NH2

P

P

O

N O

OH

O

OH OH

O

O

OH

O

OH

CH3

(R)-HPMPO-DAPy

PMEO-DAPy

(R)-PMPO-DAPy

NH2 N

O

HO P

O

N N

O

HO

HO

5-Aza-(S)-HPMPC

Fig. 25: Acyclic nucleoside phosphonates deserving further exploration


Page 35 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


35

Conclusion

The compounds reviewed here have been approved (and marketed) for the treatment of HSV infections (valacyclovir), VZV infections (BVDU), CMV infections (cidofovir), HBV infections (adefovir dipivoxil, TDF, TAF) and HIV infections (stavudine, TDF, TAF). For the treatment of HIV infections, TDF has also been launched in several drug combinations (Fig. 13-16) and so has been TAF (Fig. 18-22). The combination of TDF and emtricitabine is the only “chemical” approved for the pre-exposure prophylaxis (PrEP) of HIV infections. In addition, plerixafor (AMD3100, Fig. 11) has been approved as a stem cell mobilizer in the autologous transplantation of Non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM), and rabacfosadine (Fig. 23) is marketed for the treatment of NHL in dogs.

Acknowledgments

I thank Mrs. Myriam Cornelis for her proficient editorial assistance.

List of abbreviations ACV, acyclovir; AMD, AnorMeD; AZT, azidothymidine; BVDU, (E)-5-(2-Bromovinyl)-2'-deoxyuridine; CMV,

cytomegalovirus;

cPrPMEDAP,

9-(2-phosphonylmethoxyethyl)-N(6)-cyclopropyl-

2,6,diaminopurine; d4T, 2',3'-dideoxy-2’,3’-didehydrothymidine; DAP, 2,6-diaminopurine; ddC, zalcitabine; ddI, didanosine; DHPA, S-9-(2,3-Dihydroxypropyl)adenine; (-)FTC, (-)5-fluoro-3’thiacytidine; HBV, hepatitis B virus; HEPT, 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine; HIV, human immunodeficiency virus; HSV, herpes simplex virus; MM, multiple myeloma; NHL, nonHodgkin’s lymphoma; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside



Page 36 of 50

36 reverse transcriptase inhibitors; PMEA, 9-(2-phosphonomethoxyethyl)adenine; PMEG, 9-(2phosphonomethoxyethylguanine;

(R)-PMPA,

(R)-9-(2-phosphonomethoxypropyl)adenine;

(R)-

PMPDAP, (R)-9-(2-phosphonomethoxypropyl-2,6-diaminopurine; (S)-HPMPA, (S)-9-(3-Hydroxy-2phosphonomethoxypropyl)adenine;

(S)-HPMPC,

(S)-1-(3-hydroxy-2-

phosphonomethoxypropyl)cytosine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TIBO, tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(IH)-one; VACV, valacyclovir; VZV, varicellazoster virus.

Biography Erik De Clercq, since 2007 (until present), has been teaching the course of “Chemistry at the Service of Medicine” at the Faculty of Sciences at the University of South Bohemia (České Budějovice, Czech Republic) in a joint program with Keppler University (Linz, Austria). He received in 2010 jointly with Dr. Anthony S. Fauci the Dr. Paul Janssen Award for Biomedical Research. He has (co)discovered a number of antiviral drugs currently used in the treatment of HSV (valaciclovir), VZV (brivudin), CMV (cidofovir), HBV [adefovir dipivoxil, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF)], and HIV infections (TDF, TAF). The combination of TDF with emtricitabine (Truvada®) has been approved worldwide for the prophylaxis of HIV infections (PrEP).

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38 13

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De Clercq, E. and De Somer, P., Antiviral activity of polyribocytidylic acid in cells primed with polyriboinosinic acid. Science 1971, 173, 260-262.

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20

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22

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39 24

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25

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27

De Clercq, E., Descamps, J., De Somer, P. and Holý, A., (S)-9-(2,3-dihydroxypropyl)adenine: an aliphatic nucleoside analog with broad-spectrum antiviral activity. Science 1978, 200, 563565.

28

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De Clercq, E., S-Adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents. Biochem. Pharmacol. 1987, 36, 2567-2575.



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40 31

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Fifty years in search of selective antiviral drugs

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