Editorial pubs.acs.org/jmc
Introduction to Hepatitis C Virus (HCV) Therapies Special Thematic Issue
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to achieve approval (telaprevir and boceprevir).5,6 The identification and optimization of peptidomimetic productbased inhibitors by Boehringer-Ingelheim led to BILN-2061, which established clinical proof-of-concept for NS3 inhibitors.7,8 This advance coupled with the rapid solution of the crystal structure of NS3 proved to be highly enabling for the design of potent and effective NS3/4A inhibitors. The eight articles in this issue relating to inhibition of NS3 encompass the efforts of six groups and include descriptions of the discovery of danoprevir and asunaprevir, as well as an informative Perspective on the discovery and development of the recently approved simeprevir. As in the case of HIV reverse transcriptase, the polymerase function of HCV NS5B has been exploited for the purposes of antiviral drug development in two ways: by the incorporation of false substrates (leading to abortive RNA chain elongation) and by allosteric inhibition. For the former, nucleoside screens using bovine viral diarrhea virus as an early surrogate for HCV served as a source of leads. Subsequent optimization efforts wrestled with the difficulty of identifying an oral agent that can serve as an efficient precursor for high and long-lasting intracellular levels of nucleotide triphosphate mimics to drive incorporation into nascent viral RNA and yet not provide false substrates or inhibitors of host enzymes leading to unacceptable side effects. This proved to be a formidable challenge, but the Pharmasset group was ultimately successful as marked by the recent approval of sofosbuvir.9,10 This issue contains three papers describing nucleoside discovery efforts that illustrate the complexities involved. Allosteric inhibition of NS5B can be achieved through binding at several sites on the enzyme, categorized according to the classic right-hand topography as in the thumb and palm regions. The 11 articles recounting the discovery of nonnucleoside NS5B inhibitors herein include the thumb site inhibitors deleobuvir, BMS-791325, TMC-647055 (site 1), and GS-9669 (site 2) and the palm site binders GSK-5852 and RG7109, all of which were selected for clinical development. The advent of subgenomic HCV replicons in 1999, described by Ralf Bartenschlager in a Perspective, represented a significant advance that markedly facilitated HCV drug discovery and development. These systems quickly became critical elements of the drug discovery process, allowing the evaluation of enzyme inhibitors in a more biologically relevant setting and providing a vehicle with which to fully examine and appreciate the potential of nucleoside- and nucleotide-based inhibitors of NS5B. Importantly, HCV replicons also provided a platform for chemical genetics screening of compound collections, a mechanistically agnostic and effective approach to lead generation for the therapy of infectious diseases.11 These endeavors have been particularly successful in identifying
edicinal chemistry has always simultaneously fascinated and frustrated its practitioners who, despite the daunting complexity and empiricism associated with optimization of molecules for use as oral drugs, remain dedicated to the task by the lofty goal of alleviating human suffering and mortality. The extraordinary increase in life expectancy since the Second World War is attributable in large part to transformative medicinal advances that include the discovery and development of antibiotics and widespread use of antihypertensive and cholesterol-lowering agents to combat cardiovascular mortality.1 More recently, the impact of pharmaceutical research in the management of HIV infection has been hailed as a major achievement for our discipline: what was once an inevitably fatal infection is now manageable indefinitely through simple, oral regimens, and the pandemic has been significantly curtailed through the use of direct-acting antivirals.2 We are now witnessing another transformative advance with the regulatory approval of the first of a series of small molecule direct acting anti-HCV agents whose use in combination regimens is essentially completely curative, promising significant benefit to individual patients and to society at large in alleviating the symptoms and costly sequellae of this widespread chronic infection. The extraordinary clinical effectiveness of combination regimens has become apparent with equally extraordinary speed as high-quality oral agents built to contemporary drug design standards have moved through clinical development. As a consequence, the set of molecules that will be used for the eradication of infection is now apparent, and this was the basis of the recognition by one of us (N.A.M.) of a unique opportunity to convene the discovery stories behind several important clinical candidates and other key advances in the field into a thematic issue in the Journal of Medicinal Chemistry. The response of the medicinal chemistry community to the call for papers has been impressive, and the articles herein encompass virtually every possible approach to direct inhibition of viral infection or replication, exemplifying many of the latest techniques for lead identification as well as successful lead optimization. April 2014 marks the 25th anniversary of the report of the cloning of HCV by Michael Houghton and colleagues at Chiron in collaboration with Daniel Bradley at the Centers for Disease Control and Prevention (CDC).3 At that time, HIV research and drug development were well underway: the early nucleosides had recently been approved; the three-dimensional crystal structure of HIV protease was solved; the first protease inhibitors were about to enter the clinic. Antiviral discovery groups were therefore primed for applying the lessons learned from HIV research and development as the mechanistic details of HCV replication were elucidated.4 The first advances were made against mechanisms that could readily be recapitulated in biochemical assays (the NS3 protease and the NS5B RNAdependent RNA polymerase). For NS3 protease, covalent strategies based upon prior experience with other serine proteases ultimately led to the first direct-acting HCV agents © 2014 American Chemical Society
Special Issue: HCV Therapies Published: January 31, 2014 1625
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Journal of Medicinal Chemistry
Editorial
(6) Venkatraman, S.; Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu, Y.-T.; Lovey, R.; Hendrata, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto, P.; Popov, V.; Pike, R.; Ruan, S.; Santhanam, B.; Vibulbhan, B.; Wu, W.; Yang, W.; Kong, J.; Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.; Agrawal, S.; Ingravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.; Guo, Z.; Prongay, A.; Madison, V.; Broske, L.; Cui, X.; Cheng, K.-C.; Hsieh, Y.; Brisson, J.M.; Prelusky, D.; Korfmacher, W.; White, R.; Bogdanowich-Knipp, S.; Pavlovsky, A.; Bradley, P.; Saksena, A. K.; Ganguly, A.; Piwinski, J.; Girijavallabhan, V.; Njoroge, F. G. Discovery of (1R,5S)-N-[3-amino1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection. J. Med. Chem. 2006, 49, 6074−6086. (7) Llinàs-Brunet, M.; Bailey, M.; Fazal, G.; Ghiro, E.; Gorys, V.; Goulet, S.; Halmos, T.; Maurice, R.; Poirier, M.; Poupart, M.-A.; Rancourt, J.; Thibeault, D.; Wernic, D.; Lamarre, D. Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors. Bioorg. Med. Chem. Lett. 2000, 10, 2267−2270. (8) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bös, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A. M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagacé, L.; LaPlante, S. R.; Narjes, H.; Poupart, M. A.; Rancourt, J.; Sentjens, R. E.; St George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C. L.; Llinàs-Brunet, M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003, 426, 186−189. (9) Sofia, M. J.; Chang, W.; Furman, P. A.; Mosley, R. T.; Ross, B. S. Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-polymerase. J. Med. Chem. 2012, 55, 2481−2531. (10) Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H. R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Steuer, H. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2′-deoxy-2′-α-fluoro2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 7202−7218. (11) Keller, T. H.; Shi, P.-Y.; Wang, Q.-Y. Anti-infectives: Can cellular screening deliver? Curr. Opin. Chem. Biol. 2011, 15, 529−533. (12) Volk, M. L.; Tocco, R.; Saini, S.; Lok, A. S. F. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology 2009, 50, 1750−1755.
inhibitors of several of the nonstructural proteins that demonstrate no enzymatic function but that are clearly critical for virus replication. Included in this issue are articles describing the optimization of NS4B inhibitors by three different groups, while the discovery campaigns that led to the identification of the clinically evaluated NS5A inhibitors daclatasvir, ledipasvir, GSK-2336805, and ombitasvir are captured, a field also highlighted in a Perspective article. Beyond direct inhibition of HCV replication, other means of eliciting an antiviral effect have also been explored. An additional Perspective by Thomas Hermann illuminates approaches to targeting the internal ribosomal entry site (IRES) of HCV RNA with inhibitors, while an article on type 3 phosphatidylinositol 4-kinase α (PI4KIIIα) inhibitors summarizes an approach exploiting the virus’ dependence on a host cell enzyme. The articles collected in this thematic issue exemplify a range of techniques that are utilized in contemporary drug design, discovery, and development and capture several important components of combination therapies that are in late stage clinical trials. The panoply of direct acting antiviral agents that have emerged over the past 15 years provides an impressive example of the ingenuity and commitment of the drug discovery community to bring forward agents that are being combined into effective cures for a chronic infection that in the absence of effective therapy was predicted to be a substantial global health and economic burden.12 We thank Gunda I. Georg and Shaomeng Wang, Editors of the Journal of Medicinal Chemistry, for their support and guidance throughout the process of assembling this issue and Mark C. Livingston and Sandy K. Dewing, editorial assistants of the Journal, for so effectively managing the flow of manuscripts. Finally, we express our deep gratitude to the authors of the articles themselves who have taken considerable time and effort to describe their studies and without whom the issue would not have been possible.
Nicholas A. Meanwell, Guest Editor
Bristol-Myers Squibb Research and Development
William J. Watkins, Guest Editor
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Gilead Sciences
AUTHOR INFORMATION
Notes
The views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Cutler, D. M.; Meara, E. Changes in the age distribution of mortality over the 20th century. NBER Working Paper Series, Working Paper 8556; National Bureau of Economic Research: Cambridge, MA, 2001; http://www.nber.org/papers/w8556. (2) De Clercq, E. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int. J. Antimicrob. Agents 2009, 33, 307−320. (3) Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Isolation of a cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome. Science 1989, 244, 359− 362. (4) Watkins, W. J.; Desai, M. C. HCV versus HIV drug discovery: Déjà vu all over again? Bioorg. Med. Chem. Lett. 2013, 23, 2281−2287. (5) Kwong, A. D.; Kauffman, R. S.; Hurter, P.; Mueller, P. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat. Biotechnol. 2011, 29, 993−1003. 1626
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