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Cite This: J. Med. Chem. 2018, 61, 5093−5107
High Mobility Group Box-1 (HMGb1): Current Wisdom and Advancement as a Potential Drug Target Miniperspective Sonya VanPatten* and Yousef Al-Abed
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Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, United States
ABSTRACT: High mobility group box-1 (HMGb1) protein, a nuclear non-histone protein that is released or secreted from the cell in response to damage or stress, is a sentinel for the immune system that plays a critical role in cell survival/death pathways. This review highlights key features of the endogenous danger-associated molecular pattern (DAMP) protein, HMGb1 in the innate inflammatory response along with various cofactors and receptors that regulate its downstream effects. The evidence demonstrating increased levels of HMGb1 in human inflammatory diseases and conditions is presented, along with a summary of current small molecule or peptide-like antagonists proven to specifically target HMGb1. Additionally, we delineate the measures needed toward validating this protein as a clinically relevant biomarker or bioindicator and as a relevant drug target.
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HMGb1 AS AN IMMUNE SYSTEM SIGNAL (DAMP) Inflammation is a natural and necessary response to invading pathogens and trauma/tissue damage and is manifested by an organism’s immune system. Many aspects of the initiation of inflammation and its resolution have been revealed, yet these multifaceted reactions still hold many obscurities. Pathogenassociated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs),1 and homeostasis-altering molecular processes (HAMPs)2 are signals the innate immune system uses to recognize these threats to the health of an organism. Upon detection of an inflammatory signal, whether it be DAMP/PAMP or HAMP related, or a proinflammatory mediator (cytokines/chemokines or a modified protein (oxidized or glycated) or lipid), the immune system generally responds with a proportional feed-forward amplification and expansion of the response through pattern recognition receptors (PRRs) and other innate immune receptors, cytokine receptors, and/or inflammasome pathways. To turn off the inflammatory process, the sensing and switching of a proinflammatory response into the resolution phase, as well as activation of anti-inflammatory pathways, have begun to be elucidated, though much remains to be explored.3,4 The current understanding of the dangers of excessive acute inflammation and unresolved chronic inflammation is well described in the literature in numerous diseases and conditions. HMGb1 was first described as playing an extracellular role in inflammation in 1999 when it was discovered as a late mediator of sepsis,5 although its initial characterization was as an intranuclear non© 2017 American Chemical Society
histone protein that could directly bind DNA. This multifunctional protein is now known for its roles in the nucleus (transcription factor, transcription enhancer, nucleosome sliding, DNA repair, V(D)J recombination, telomere homeostasis),6 cytoplasm (autophagy,7 viral sensing8), and extracellular milieu (DAMP secreted or released by cell damage).9 HMGb1’s nuclear function is nearly ubiquitous, and the protein in totality is necessary for life as complete knockout of the gene results in lethality due to hypoglycemia after birth.10 Tissue specific conditional knockouts have been successfully generated however.11 Various inflammatory signals may initiate export of nuclear HMGb1 to the cytoplasm and culminate in extracellular secretion. Nuclear export has been shown to be regulated by oxidation, ADP-ribosylation, phosphorylation, secondary messengers (reactive oxygen species (ROS), Ca2+, nitric oxide (NO)), as well as by both acetylation and methylation.12−14 The oxidative/reduced state of three critical cysteine residues (yellow highlight, Figure 1) has proven a major regulator of specific cellular death related pathways. The all-thiol form where all three cysteines are reduced is associated with autophagy and/or HMGb1’s extracellular chemokine-like chemotactic activity (via CXCL12/CXCR4 and receptor for advanced glycation endproducts (RAGE)), while the disulfide form, in which C23 and C45 form an intrachain bond, relates to its extracellular proinflammatory cytokine-inducting activity via Received: August 3, 2017 Published: December 21, 2017 5093
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Figure 1. Model and schematic view of HMGb1 structure with box regions and cysteine residues highlighted.
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ANTI-INFLAMMATORY PATHWAYS AND INFLAMMATION RESOLVING FACTORS In order to resolve an inflammatory response, damage and pathogens must be cleared and activated cells need to be removed or reprogrammed to an inert, resting state. The sequential induction of resolvin-type mediators26 in the normal immune response helps to achieve this endpoint along with activation of anti-inflammatory signals and pathways.3,4 A few of the main anti-inflammatory pathways that serve to antagonize the proinflammatory response include induction of numerous inhibitory miRNAs, SOCS proteins,27 activation of the hypothalamic−pituitary axis (HPA) (i.e., by cytokines) leading to adrenal corticosteroid production and glucocorticoid receptor activation, resulting in inhibition of proinflammatory gene expression (reviewed in ref 28), and stimulation of the cholinergic anti-inflammatory pathway (CAP).29 Some of these anti-inflammatory responses are known to regulate HMGb1 levels directly (miRNAs,30 SOCS,31 CAP32). Many insights into the molecular pathways of the anti-inflammation/resolution phase have occurred over recent years, including the observation that adaptive immunity is achieved during the post-resolution phase. Nonresolving inflammation or “frustrated resolution” occurs when inflammatory signals are not cleared or switched off and the resolution phase does not progress, hindering the development of adaptive immunity.33
the extracellular RAGE or Toll-like receptor 4 (TLR4). The fully oxidized form has thus far been associated with apoptosis.13 The HMGb1 protein contains two similar yet distinct DNA-binding domains, termed A-box and B-box, each containing three α helices that fold into an L or V shaped structure (Figure 1, 3D model created using Cn3D version 4.3.1 and PDB code 2YRQ). It also contains a negatively charged acidic tail that interacts with specific residues within and between the HMG boxes and thus regulates the 3D structure and DNA binding of the protein. These and additional biochemical and structural aspects of HMGb1 have been reviewed extensively elsewhere.12,14
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INITIATION AND EARLY EVENTS IN INFLAMMATION In the initial insult of trauma or pathogen exposure, DAMPs, PAMPs, and HAMPs signal PRRs on platelets,15,16 neutrophils, macrophages/monocytes, and many other cell types.17 Platelets have also been shown to actively export HMGb1 to the cell surface after activation,18 which leads to recruitment of other immune cells and amplification of the initial activation signal. Neutrophils are another early responder in inflammation (including sterile), and the generation of neutrophil extracellular traps (NETosis) initiates a series of events that have been reviewed extensively.19 Other extracellular factors such as acute phase proteins (fetuin A, C-reactive protein (CRP), serum amyloid A (SAA)20), pentraxin3 and complement factors,21 endogenous glucocorticoids,22 and cytokines/chemokines serve to coordinate and further regulate the initial inflammatory signal. Pattern recognition receptors including TLRs and RAGE bind HMGb1 and other PAMPs and DAMPs including DNA, dsRNA, LPS, flagellin, peptidoglycan, S100 proteins, heat shock proteins (HSPs), uric acid, ROS, advanced glycation endproduct (AGE)-modified proteins, and celladhesion molecules and may also signal and influence the overall inflammatory response. HMGb1 alone has been shown to propagate the inflammatory response by inducing the synthesis of CRP, TNFα, IL-6, and MIP1α and -β in human monocytes.23 Moreover, HMGb1 is also capable of modulating the adaptive (acquired) immune response.24,25
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ENDOGENOUS MODULATION OF HMGb1 ACTIVITY AND SIGNALING HMGb1, which normally resides in the nucleus, can be translocated to the cytoplasm in response to various stimuli that regulate its post-translational modifications including acetylation,34 methylation,35 phosphorylation,36 and redox modification (reviewed in ref 37). The upstream signals that result in these post-translational modifications (PTMs) may include infection or trauma (sterile injury) resulting in release of PAMPs/DAMPs, oxidative or osmotic stress, ATP excess or depletion (starvation), and/or ischemia/reperfusion (reviewed in ref 38). Additional levels of regulation may include pathways of degradation and cleavage,39 interaction with binding partners,40 or other receptors (CD24/Siglec,41 syndecans,42 5094
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Table 1. Human HMGb1 Associated Diseases and Conditions (Not Comprehensive)a disease/condition Alzheimer’s
receptors/signaling pathways implicated
Tau and amyloid-β colocalization with HMGb1 (separately) TLR2 and -4 and RAGE
ALS
serum/tissue levels (disease vs control, ng/mL)
*sRAGE interference in measurement?
ref *98
brain, ↑1.5-fold vs control
99 100
spinal cord, ↑mRNA and protein staining in slow-progressing ALS samples vs controls ↑ protein expression (2- to 3-fold) vs control
101 102
synovium-mRNA and protein ↑approximately 2-fold vs control synovial fluid cartilage, 100× ↑mRNA by qPCR vs control serum (3.4 vs 0.8), p = 0.0014
103 104 105 106
synovial fluid (54) in RA vs (12) in OA, p < 0.01 plasma (6.30 vs 3.71) plasma and tissue expression (protein) correlated with worse overall and progression-free survival, meta analysis and systemic review
107 108 109
arthritis osteo (OA)
juvenile idiopathic (JIA) rheumatoid (RA) asthma cancer cardiac disease coronary artery disease (CAD) atherosclerosis diabetes type 1
type 2 lung related diseases COPD pulmonary hypertension pneumonia
ICU patients (various conditions) heart failure acute coronary ischemia infection inflammatory bowel disease ulcerative colitis (UC) Crohn’s disease (CD) ischemia/reperfusion injury (transplant or trauma) kidney failure
liver failure
mild cognitive impairment (pre-Alzheimer’s) multiple sclerosis obesity/metabolic syndrome pancreatitis
110 serum (5.45 vs 2.33), p < 0.01
111
plasma, higher levels in T1D when normalized for confounding factors, plasma levels associated with all cause mortality plasma (0.2 vs 0.13 nmol/L), p < 0.01 plasma (8.27 vs 4.57), p < 0.001, obese + type 2 vs type 2 (9.11 vs 7.4), p < 0.001 plasma (15.31 vs 4.82), p < 0.001
112
sputum (15.15 vs 0.41) serum (severe PAH-CHD 19.12*, mild to mod PAH 8.54*, CHD 5.35**, vs 3.76), p < 0.001*, p < 0.05** pediatric serum (severe pneumonia 22.5 vs uncomplicated influenza 8.61) plasma (community acquired 184.0 vs 11.2), p = 0.0001 plasma (peak ALI/ARDS 13.7 vs onset 2.9 vs controls, nondetectable) plasma (6.3 vs 2.8)
108 116
113 114 115
117 118 119 120
serum (7.57 vs 2.66) serum (31.39 (NYHA class IV), 28.72 (groups total) vs 25.71)) (ng/mL = μg/L) serum (159 vs 1.94), p < 0.001 serum (17.4 (H1N1, groupA) vs 5.5) fecal (significantly increased in UC and CD patients vs healthy controls and correlated with endoscopic inflammation index)
121 122 123 124 125
plasma (CD 26, UC 27 vs 7), p < 0.01 liver transplant (caval effluent 188 vs portal vein 3), p < 0.001
126 127
serum, pediatric dialysis patients, effect of peritonitis (baseline dialysis patients 9.5 vs preperitonitis 32.1 vs T.1 (during) 64 vs T-end of peritonitis 36,), p < 0.0001 serum (AKI 5.8 vs CKD 3.2 vs hemodialysis 2.5 vs controls 1.7), p < 0.001 kidney transplant, staining (increased in deceased donor kidneys vs living kidney donors) serum (CKD grade 5, 146.7 vs CKD grade 3/4, 85.6 vs control, 10.9), p < 0.001 pediatric serum, HMGb1 found as central inflammatory mediator (node) in all patient subgroups of acute ALF serum, ALF (3.0 vs 0.3), p < 0.0001 ALF SIRS score 2 (3.8 vs 11), p = 0.0083 serum, acute liver failure vs acute self-limiting viral hepatitis E vs controls (225.3 vs 112.6 vs 12.04), p < 0.0001 serum (approx 5.5 vs 3), p < 0.01
128
brain macrophages, ↑4-fold protein staining vs controls (μg/mm2), p < 0.0001 CSF mononuclear cell mRNA ↑∼2-fold vs controls, p < 0.0001 serum (19.4 vs 3.7), p < 0.0001 HMGb1 correlated with BMI serum (5.4 vs 1.7) (6.02 vs 1.87)
135
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129 130 131 132
133 134 98
136 137 138
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Table 1. continued disease/condition
receptors/signaling pathways implicated
pregnancy complications (preeclampsia) sepsis
SLE
spinal cord injury stroke trauma (blunt chest)
traumatic brain injury
serum/tissue levels (disease vs control, ng/mL)
ref
serum? (12.05 vs 9.47)
139
serum (nonsurvivors 83.7 vs survivors 25.2 vs controls, nondetectable), p < 0.05 serum levels associated with no. of organ failures (SOFA scores) serum (DIC 14.05 vs control, not detectable) increased in sepsis nonsurvivors compared with survivors controversy, levels in sepsis vs septic shock, review serum (30.14 vs 5.09), p < 0.05 serum, renal involvement vs nonrenal SLE (42.6 vs 15.7), p < 0.05 serum (27 vs 0), p < 0.001 plasma (5.84 vs 4.45), p = 0.037 plasma, active SLEDAI vs inactive SLE vs controls (6.44 vs 4.42 vs 4.45), p = 0.039, 0.049, 0.006, respectively serum (108 vs 13), p < 0.0001 plasma (0−3 days postinjury, 6 vs 4−7days post, 6.26 vs controls, 1.26), p < 0.01 serum (218 vs 16.8), p < 0.001 plasma, increased over 1−7 days (day 1, 43.8 to day 7, 74.4) postinjury, no normal controls measured plasma (10.4 vs 1.4), p < 0.0001; 1yr mortality (9.0 (survivors) vs 14.6 (nonsurvivors)), p < 0.001 pediatric CSF (5.73 vs 1.78) at 0−24 h, p < 0.05
5 140 141 142 143 144 145 146 147
148 123 149 150 151
a
ALS, amyotrophic lateral sclerosis; PAH, pulmonary arterial hypertension; CD, Crohn’s disease; UC, ulcerative colitis; CHD, coronary heart disease; AKI, acute kidney injury; CKD, chronic kidney disease; ALF, acute liver failure; ALF-SIRS, ALF-systemic inflammatory response syndrome; SLE, systemic lupus erythematosus; SLEDAI-SLE, disease activity index; CSF, cerebrospinal fluid; SOFA, sequential organ failure assessment; DIC, disseminated intravascular coagulation.
Table 2. Directly-Binding HMGb1 and HMGb1-Receptor Small-Molecule and Peptide-Based Antagonists inhibitor
target/targeted region (measured affinity)
ref
glycyrrhizin methotrexate metformin inflachromene (1d) compounds 2j and 2l (inflachromene derivatives) EGCG (green tea) salicylic acid (SA) and analogues heparin (glycolipid) eritoran (glycolipid) FP7 (glycolipid) TAK-242
HMGb1 (A and B box) (Kd, with A box = 103 ± 25 μM, with B box = 87 ± 35 μM) HMGb1, Al and Bj regions (Kd, A1 = 0.5 ± 0.3 μM, Bj = 0.024 ± 0.01 μM) HMGb1 HMGb1 and HMGb2 HMGb1 (order of potency: 2j > 2l > 1d) HMGb1, Cys106 region HMGb1, A box and B box, all thiol and disulfide forms (SA Kd ∼ 1−10 μM, 3AESA Kd = 1.48 nM) HMGb1, amino acid residues 6−12 (KD = 4.5 nM) TLR4 via MD2, *no effect in phase III clinical study of severe sepsis TLR4 via MD-2/CD-14 TLR4/TIR domain, phase III study suspended
TAPs (peptide-based) MNP M2000 P5779 (peptidomimetic) ZINC library compounds (virtual screen > in vitro confirmation) azeliragon (Pf04494700) FPS-ZM1 A box (peptide) R2F8
TLR4/MD-2 (TAP2/MD2-TLR4, KD = 5.95 μM) TLR4 dimerization TLR2/4 (TLR4) via MD-2-Tyr102 (with MD2 Kd = 0.65 μM) TLR4/MD-2 (zinc compounds T5342126, 25778142, 49563556, 3415865) RAGE-amyloid β interaction, *low dose still in phase III trials, reported (internal report) to block RAGE-HMGb1 interaction161 RAGE/V-domain (blocked RAGE-amyloid β binding akin to HMGB1 antagonist) RAGE, TLR? RAGE-HMGb1 interaction (fibronectin type iii scaffold based inhibitor, nonspecific)
S100-based peptides
RAGE-HMGb1 interaction
Mac-1,43 TLR244). Recently two other proteins have been demonstrated to interact with extracellular HMGb1 and may serve as a form of regulation in specific conditions. Thrombomodulin, a regulator of coagulation, can bind HMGb1 and thereby reduce its inflammatory activity by sequestering it from binding other receptors (reviewed in ref 45). Additionally haptoglobin, an acute-phase protein that
69 72 78 68 73 77 74 70, 152 153 154 reviewed in ref 155 156 157 158 79 159, 160 reviewed in ref 162 163 39, 164, 165 mentioned in ref 82 166
binds free hemoglobin to prevent oxidative damage, can also scavenge extracellular HMGb1thereby reducing inflammatory signals.46 The concept of intracellular molecular signaling hubs that integrate survival and death signals, leading to generation of the appropriate cellular response, has been proposed.47 These signals, combined with the subsequent amounts of HMGb1 5096
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Figure 2. Structures of direct HMGb1 antagonists.
passively released (necrosis) or secreted, have been shown to regulate whether necroptosis, pyroptosis, apoptosis, NETosis,
or autophagy pathways are initiated in surrounding areas. One particular signal integration hub involves regulation of intra5097
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line with an IC50 of approximately 50 μM. Additional studies showed only a mild effect of the compound on DNA/HMGb1 binding. The binding region on HMGb1 is described as occurring at the crux of the L-fold which has an exposed hydrophobic surface amenable to van der Waals interactions with glycyrrhizin. The structurally related compound carbenoxolone (glucuronic acid substituted with succinyl moiety) was found to bind A box in a manner similar to glycyrrhizin, but data for B box were less clear and showed evidence of aggregation at higher concentrations.69 Heparin, an endogenous sulfated glycosoaminoglycan anticoagulant (3−30 kDa) that has been adapted for clinical use (approximate MW of 1.5 kDa), was shown to inhibit HMGb1-induced TNF and IL-6 secretion using an in vitro assay with RAW264.7 macrophages and HUVEC cells in 2011. A direct heparin-HMGb1 interaction was demonstrated with surface plasmon resonance (SPR) experiments, circular dichromism (CD) spectroscopy, and binding studies monitoring tryptophan and tyrosine florescence. SPR gave an estimated KD of 4.5 nM. HMGb1 amino acid residues 6−12, which contain a consensus sequence similar to other heparin-binding proteins, were responsible for heparin binding, and heparin successfully competed with RAGE binding to HMGb1.70 The heparin binding ability of HMGb1 (previously termed p30/ amphoterin) was first realized back in 198771 before any of its extracellular proinflammatory roles were realized, when it was fractionated out with a heparin-Sepharose column in a screening for neurite outgrowth promoting factors. In 2013, the autoimmune disease and cancer drug methotrexate (Mtx), a biguanidine-folic acid-like derivative known for inhibition of dihydrofolate reductase, deoxycytidine kinase, and nuclear factor κ-light-chain-enhancer of activated B cells (NFκB), was shown to also interact with and inhibit HMGb1. Binding between HMGb1 and Mtx was observed using SPR analysis and electromobility shift assays (EMSA), while docking studies provided further evidence for a direct interaction. Two distinct noncooperative binding sites in the Al(1−87aa) and Bj(88−181aa) box regions were measured with Kd’s of 0.5 ± 0.3 μM and 0.24 ± 0.01 μM, respectively. Functionally, Mtx inhibited HMGb1-induced TNFα secretion and mitogenic activity, and this was likely through interaction with the RAGE receptor as Mtx did not inhibit LPS-induced TNFα release (TLR4 dependent). Furthermore, Mtx was not found to inhibit HMGb1 binding to DNA.72 The inflachromene series of HMGb1 antagonists was first reported in 2014. These pentacyclic triazolidine-dione-based class of compounds were found in a cell-based phenotypic screening for neuroinflammatory inhibitors in an LPS-induced microglial cell stimulation assay. Inflachromene (ICM-1d) suppressed LPS-induced nitrite release as well as cytokine production in microglial cell lines, primary microglia, and macrophage cell lines. To identify the cellular targets, a photocross-linking analogue of ICM was created using structure− activity relationship (SAR) studies and used to pull out HMGb2 (among others). Additional studies using an ICMlinked column proved HMGb2 could be successfully competed out with nonbound ICM, demonstrating its specificity. On the basis of structure-sequence homology, HMGb1 was speculated to also bind ICM. This was shown functionally by using siRNA knockdown of either or both HMGb1 and -2 to prove that ICM lost inhibitory ability on LPS-induced nitrite release after HMGb1/2 knockdown. It was also discovered that ICM directly inhibited post-translational modifications on HMGb1
cellular calcium levels.48 The cell’s ability to buffer calcium levels, via modulation of ion channel opening and/or synthesis/ release of Ca2+ binding proteins, serves a critical role in signal propagation, cellular functions, and cell fate (survival vs death49). Calcium signaling is crucially involved in a myriad of cellular processes including survival/repair, proliferation, differentiation, death pathways, normal metabolism, gene transcription, signaling pathways (protein phosphorylation), stimulus-induced protein secretion, neurotransmission, and motility. HMGb1 can itself be regulated by calcium signaling36,50,51 and also induce calcium-related signaling through different receptors and downstream pathways (TLRs,52−55 RAGE,56 CXCL12/CXCR4,57 transient receptor potential (TRP) channels58). The precise involvement of calcium signaling pathways (interrogated via chelating agents, or specific calcium channel blockers) in different cell types and environments, and in response to different HMGb1 levels, still requires some elucidation but appears to be highly context dependent.
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HMGb1 AND EXTRACELLULAR HMGb1 RECEPTORS AS DRUG TARGETS The relevance of HMGb1 as a significant drug target and potential biomarker has been demonstrated by measuring its increase extracellularly in plasma/serum and tissue in human diseases and pathological conditions. These include neurodegenerative disease, arthritis, autoimmune diseases, lung injury and disease, cancer, cardiac and vessel disease, diabetes (type 1 and type 2), trauma/ischemia−reperfusion injury, infection, kidney and liver-related disease, pancreatitis, and pregnancy complications (Table 1). HMGb1-directed therapies, focusing on those that directly bind and neutralize extracellular HMGb1 (including antibodies), have been tested in preclinical models of the above-listed, as well as other diseases and conditions. The myriad of potential benefits of HMGb1-specific drugs and therapies is well supported in the scientific literature.59−63 We provide a summary of directly binding, peptide-based and small-molecule, HMGb1-targeted therapeutics in Table 2. Some of these are approved drugs that were found to have off-target effects by directly binding HMGb1, while others have only been tested preclinically. The structures of these directly binding HMGb1 inhibitors are illustrated in Figure 2. Going forward, HMGb1directed therapies with minimal off-targets should be used to reinforce the value of HMGb1 as a specific and effective drug target. An additional point, HMGb1 family member, HMGb2, is highly similar in structure/sequence, and its expression and contribution to inflammation and disease is beginning to be reported.64−67 Equivalent PTMs and receptor binding for HMGb2 can be assumed from sequence similarity (http:// www.uniprot.org/uniprot/p26583). The specificity of HMGb1directed small molecules and peptides for HMGb2 is scant68 and could possibly be exploited for selective targeting as more is learned. The first directly binding HMGb1 antagonist to be described in the literature was the glycoconjugated triterpene glycyrrhizin, a compound that occurs naturally in the licorice plant. It was found using NMR chemical shift data to bind to both the A and B boxes with Kd’s of 103 ± 25 μM and 87± 35 μM, respectively. This binding was also found to be independent and noncooperative and involved residues F17, Q20, R23, E25, K43, and C44 on the A box and residues R109, I112, D123, and A125 on the B box. Glycyrrhizin inhibited the HMGb1-induced chemotactic and mitogenic activity in the 3T3 fibroblast cell 5098
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Figure 3. Structures of indirect HMGb1 antagonists.
and -2 responsible for cytosolic and extracellular translocation. Compared to glycyrrhizin, ICM had 600× more potency on
microglia and docking studies predicted binding at the DNA binding domain in box A adjacent to a nuclear localization 5099
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sequence (NLS) where PTMs occur.68 In 2016, this group expanded their SAR studies and identified two additional ICM analogues (2j and 2l) with improved solubility and microsomal stability, tighter functional binding and lower energies (modeling). In the cecal ligation and puncture (CLP)-sepsis model the new ICMs (2j, 2l) showed 74% and 56% survival rates compared with 45% for the original ICM (1d) compared with control values (vehicle) of 10%.73 Salicylic acid (SA) (the endogenously deacetylated product of aspirin (acetylsalicylic acid)) and both synthetic (3aminoethyl (AE)-SA) and natural (amorfrutin-B1) analogues of SA were discovered to bind HMGb1 in 2014. This added to the already known anti-inflammatory actions of aspirin through COX1/2 inhibition. The interaction was found using an SAcross-linked column affinity pulldown/competition analysis and was also measured using NMR and SPR. Although Kd’s for SA were estimated in the low mM range, the SA analogues 3-AESA and amorfrutin B1 had Kd’s in the nM range. These authors found that SA and the select analogues had the same separate binding sites in both the A and B boxes of HMGb1. Additionally, SA and analogues could inhibit the chemoattractant activity of fully reduced HMGb1 (via CXCL12/ CXCR4), as well as the cytokine-inducing effect of disulfide HMGb1 (via MD2/TLR4). This biological inhibition was deemed relevant based on estimated plasma SA concentrations after standard dose aspirin administration, while the analogues (3-AESA, amorfrutin B1) were observed to be orders of magnitude more potent.74 The popular green tea component epigallocatechin 3-gallate (EGCG) had previously been shown to inhibit the LPSinduced release of HMGb1 from macrophage/monocytes, to reduce plasma HMGb1 levels in a model of sepsis,75 and to stimulate autophagy after induction of aggregation of the protein,76 yet the mechanisms remained to be fully elucidated. The reducing agent DTT could disrupt this interaction, providing evidence that cysteine residue sulfide bonds were involved in the binding to EGCG. A computational modeling study in 2016 elaborated on the EGCG interaction using molecular dynamic simulations and potential mean force calculations to project details of the HMGb1-induced aggregation. Modeling with EGCG predicted induction of a large conformational change in the protein which caused burying of certain hydrophobic residues (including Cys106) involved with the catechin ring of EGCG and surface exposure of more charged hydrophilic residues to solution. The molecular polarity of the HMGb1 with EGCG was estimated to be twice that of protein alone; thus favorable electrostatic interactions were implicated in the observed aggregation.77 As EGCG has other known targets and is already broadly commercially available as a dietary supplement, its development and use as a clinically relevant HMGb1 inhibitor is unlikely. Another clinically approved biguanidine-containing drug, metformin, used already in metabolic disease (prediabetes) and type 2 diabetes, was discovered to bind HMGb1 in 2017. The exact cellular mechanisms by which it lowers hepatic blood glucose production and restores insulin sensitivity are not fully elucidated, but effects on the mitochondrial complex 1/gapdh/ AMPK pathway and NfκB have been reported. HMGb1 was discovered as an additional metformin target while searching for binding proteins using a biotinylated metformin, avidinlinked column pull-down assay. This interaction was shown to occur through the acidic C-terminal tail region as HMGb1 constructs lacking the tail region (HMGb1-ΔAT) could still
stimulate downstream HMGb1-induced readouts including p38 phosphorylation and TNFα production; however administration of metformin with HMGb1-ΔAT no longer had any inhibitory effects on those readouts. These authors also established that metformin did not influence the redox state of HMGb1 and demonstrated that binding was noncovalent in nature using mass spectrometry.78 Two of the most prevalent and well-studied HMGb1 extracellular receptors are TLR-4 and RAGE. These receptors likely work in conjunction and also in accordance with other factors (MD-2,79 CD-14,80 LPS81) to propagate downstream inflammatory signals and effects.82 HMGb1 has also been shown to interact with CXCL-12 and mediate chemotactic responses through the CXCR4 receptor. Thus far, numerous studies have confirmed the importance of HMGb1 receptor antagonists in diverse disease models. A more general review of small-molecule TLR4 and RAGE antagonists is described in refs 83 and 84. Furthermore, antibody-based antagonists against TLRs, and also RAGE, show efficacy in models including neurodegeneration (AD 85 ), liver injury, kidney injury, ischemia/reperfusion injury (trauma), multiple sclerosis (EAE), acute lung injury, xenograft/transplant rejection, systemic inflammation/sepsis,86 asthma, myocardial infarction, and atherosclerosis to highlight a few. From a small-molecule/ peptide perspective, a summary of several more recently described TLR4-specific antagonists is listed in Table 2 and structures are presented in Figure 3. Past reviews describe other TLR4-specific antagonists from previous years.87−89 RAGE antagonists are less abundant than those directed at the TLRs, yet also offer potential in the anti-inflammation field and are summarized in Table 2 with structures in Figure 3. Other isoforms (splice variants) of RAGE, i.e., soluble RAGE (sRAGE) and RAGEΔICD,90 have been shown to function as a competitive inhibitors of RAGE-ligand binding to signaling-competent RAGE by acting as decoys for HMGb1 binding. Thus, regulation of RAGE splicing can provide another level of control by the organism to influence extracellular HMGb1 levels. As both TLR and RAGE receptors bind other ligands, their inhibition may have much broader effects, the advantage or disadvantage of which, in each specific disease, remains to be determined. The ability of HMGb1 to bind CXCL12 and activate CXCR4 chemotactic and migratory responses serves as a potential target for specific antagonist development.91 Future research is needed to design antagonists that specifically block HMGb1CXCL12 binding; however general CXCR4 antagonists (Table 2, Figure 3) are a growing domain in cancer, autoimmune, HIV, and neuroinflammation research.92
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ACHIEVEMENTS AND REMAINING CHALLENGES TO REALIZING HMGb1 AS A BIOMARKER/BIOINDICATOR AND DRUG TARGET The search for biological targets that are upregulated in disease conditions and can be used as biomarkers/indicators of disease activity or exploited for design of small molecule or proteinbased antagonists is best exemplified by the development of the tumor necrosis factor (TNF) α antagonists. While generally effective for some patients in many inflammatory diseases, longterm use may lead to an increased risk of infections and/or malignancy.93,94 Moreover, in certain inflammatory conditions, antagonism of TNFα (an early phase proinflammatory factor) proves ineffective as it is believed that later stage mediators 5100
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Table 3. Steps toward HMGb1 as a Clinical Biomarker/Bioindicator and Advancement as a Drug Target timeline of end points
supporting refs
(1) Standardize assay for serum/plasma and tissue levels with consideration for PTM form, interfering factors#, and time of sampling after initial trauma or disease flare (mass spec*, Ab-based?) (2) FDA approval of a standardized kit (ELISA) or clinical testing method (MS) (3) Measurement in different diseases/conditions through clinical trials using validated assay (4) Correlation and conclusions (reporting through publications) from medium to large scale clinical trial analyses
#
95, 167, *168−171
Assay with most potential,172 review of MS methods173 Review of FDA-approved clinical protein assays174 Analyses of publication rates after NIH clinical trials175,176
(5) Pending positive study outcomes, education of appropriate clinical professionals about HMGb1 as a biomarker/indicator, and further development as a drug target in validated diseases/conditions
not prove direct correlations with disease activity. Future studies with directly binding HMGb1 inhibitors (with minimal off-targets) will be needed for validation of this specific target in each disease condition. In conclusion, HMGb1 is poised to become a relevant drug target in inflammatory-related diseases and conditions including, but not limited to, cancer, sepsis, atherosclerosis, diabetes, chronic pain, and autoimmune, neurodegenerative, and heart disease. Refinement of quantitation techniques for HMGb1 from biological samples resulting in a standardized measurement assay, and careful design, execution, and reporting of future clinical trials will ensure the successful advancement of therapeutics that target the extracellular escape and accumulation of this multifunctional protein. Design and testing of antagonists with greater HMGb1 specificity are essential, and additional development of antagonists that target regions of HMGb1’s interaction with binding partners is also an area for development.
(including HMGb1) may play a more critical role in the perpetuation of inflammation.14 HMGb1 seems primed to become the next viable candidate for an FDA-approved inflammatory biomarker/bioindicator and drug target. Current research in animal models strongly supports its critical role in inflammatory diseases and conditions, and there are several known drugs and preclinical compounds that bind and antagonize HMGb1 directly that can be used to interrogate its relevance (Table 2.). In addition, correlations of disease and disease activity with HMGb1 levels in humans have been advancing (summarized in Table 1), although further clinical studies with larger patient populations are needed. As a first step in this direction, a reliable and standardized assay for both tissue and serum/ plasma is necessary. Many studies looking at HMGb1 levels used antibody-based systems (ELISA or immunohistochemistry) employing antibodies with various or unknown specificities. Some antibodies may not give true indications of HMGb1 levels if they target regions of interaction with binding proteins such as sRAGE, etc.95 Although several ELISA-based kits are available commercially for preclinical studies, a mass spectrometry based assay would theoretically provide a more consistent measure of biological levels and also be able to distinguish PTMs when desired.96,97 The effective development of a standardized, validated clinical assay for HMGb1 is a critical first step on the path toward effective HMGb1 antagonists and therapeutics. We highlight the necessary objectives toward advancement of HMGb1 as a clinical biomarker/indicator and drug target in Table 3. At the time of this writing, the NIH Web site, https:// clinicaltrials.gov/, listed 37 studies with the query “hmgb1”. Of these, 10 studies are related to measurement of plasma HMGb1 (as either a primary or secondary outcome measure, no intervention), 26 involve some form of intervention (with plasma HMGb1 levels as either a primary or secondary outcome measurement), and 1 study was withdrawn before it was initiated. The interventions include drugs (14 studies), dietary supplements (2 studies), biologic or cell-based therapies (2 studies), exercise (1 study with results posted), rehabilitation (1 study), psychocognitive therapies (1 study), medical devices (4 studies), and 2 studies are related to amphotericin B and mistakenly use the term amphoterin B (an early term for HMGb1) and thus are not relevant, leaving the final tally at 35 HMGb1-related studies. Additional stratification reveals that of these 35 studies, 1 was withdrawn, 1 was terminated, 5 are not yet recruiting, 13 are recruiting, 8 are completed (only 1 posted results), and 7 have an unknown status. It is clear this field is still in its infancy. Furthermore, as the interventions are mainly targeted at other inflammation or cancer-related proteins and pathways, the secondary effects observed on HMGb1 levels do
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sonya VanPatten: 0000-0001-9304-4579 Notes
The authors declare the following competing financial interest(s): Dr. Al-Abed is on patents related to HMGb1 antagonists. Biographies Sonya VanPatten, Ph.D., is a research scientist at the Feinstein Institute for Medical Research in Manhasset, NY. She did her thesis work at the Albert Einstein College of Medicine in the Department of Biochemistry and her postdoctoral studies in the laboratory of Dr. Yousef Al-Abed. Her previous research has involved the fields of lipid metabolism, metabolic disease, and type 2 diabetes, as well as drug discovery and development related to inflammation and immunity. Yousef Al-Abed, Ph.D., obtained his doctorate in Organic Chemistry from Tübingen University in Germany where he focused on the synthesis of sugar-related molecules. He is currently a Professor and Head of the Center for Molecular Innovation at the Feinstein Institute for Medical Research, in Manhasset, New York. The Center leads the discovery and development of novel therapeutics for human diseases, particularly diseases with autoimmune and inflammatory components such as lupus, arthritis, diabetes, cancer, Alzheimer’s, and sepsis.
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ABBREVIATIONS USED HMGb1, high mobility group box 1; DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern; HAMP, homeostasis-associated molecular pattern; 5101
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(10) Calogero, S.; Grassi, F.; Aguzzi, A.; Voigtlander, T.; Ferrier, P.; Ferrari, S.; Bianchi, M. E. The lack of chromosomal protein hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat. Genet. 1999, 22 (3), 276−280. (11) Tang, D.; Kang, R.; Van Houten, B.; Zeh, H. J.; Billiar, T. R.; Lotze, M. T. High mobility group box 1 (hmgb1) phenotypic role revealed with stress. Mol. Med. 2014, 20, 359−362. (12) Kang, R.; Chen, R.; Zhang, Q.; Hou, W.; Wu, S.; Cao, L.; Huang, J.; Yu, Y.; Fan, X. G.; Yan, Z.; Sun, X.; Wang, H.; Wang, Q.; Tsung, A.; Billiar, T. R.; Zeh, H. J., 3rd; Lotze, M. T.; Tang, D. Hmgb1 in health and disease. Mol. Aspects Med. 2014, 40, 1−116. (13) Tang, D.; Billiar, T. R.; Lotze, M. T. A janus tale of two active high mobility group box 1 (hmgb1) redox states. Mol. Med. 2012, 18, 1360−1362. (14) Yang, H.; Wang, H.; Chavan, S. S.; Andersson, U. High mobility group box protein 1 (hmgb1): The prototypical endogenous danger molecule. Mol. Med. 2015, 21 (Suppl. 1), S6−S12. (15) Shiraki, R.; Inoue, N.; Kawasaki, S.; Takei, A.; Kadotani, M.; Ohnishi, Y.; Ejiri, J.; Kobayashi, S.; Hirata, K.; Kawashima, S.; Yokoyama, M. Expression of toll-like receptors on human platelets. Thromb. Res. 2004, 113 (6), 379−385. (16) Fuentes, E.; Rojas, A.; Palomo, I. Role of multiligand/rage axis in platelet activation. Thromb. Res. 2014, 133 (3), 308−314. (17) Newton, K.; Dixit, V. M. Signaling in innate immunity and inflammation. Cold Spring Harbor Perspect. Biol. 2012, 4 (3), a006049. (18) Rouhiainen, A.; Imai, S.; Rauvala, H.; Parkkinen, J. Occurrence of amphoterin (hmg1) as an endogenous protein of human platelets that is exported to the cell surface upon platelet activation. Thromb Haemost. 2000, 84 (6), 1087−1094. (19) Jorch, S. K.; Kubes, P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat. Med. 2017, 23 (3), 279−287. (20) Ye, R. D.; Sun, L. Emerging functions of serum amyloid a in inflammation. J. Leukocyte Biol. 2015, 98 (6), 923−929. (21) Agrawal, A.; Singh, P. P.; Bottazzi, B.; Garlanda, C.; Mantovani, A. Pattern recognition by pentraxins. Adv. Exp. Med. Biol. 2009, 653, 98−116. (22) Xavier, A. M.; Anunciato, A. K.; Rosenstock, T. R.; Glezer, I. Gene expression control by glucocorticoid receptors during innate immune responses. Front. Endocrinol. (Lausanne, Switz.) 2016, 7, 31. (23) Andersson, U.; Wang, H.; Palmblad, K.; Aveberger, A. C.; Bloom, O.; Erlandsson-Harris, H.; Janson, A.; Kokkola, R.; Zhang, M.; Yang, H.; Tracey, K. J. High mobility group 1 protein (hmg-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 2000, 192 (4), 565−570. (24) Bianchi, M. E.; Manfredi, A. A. High-mobility group box 1 (hmgb1) protein at the crossroads between innate and adaptive immunity. Immunol. Rev. 2007, 220, 35−46. (25) Manfredi, A. A.; Capobianco, A.; Bianchi, M. E.; RovereQuerini, P. Regulation of dendritic- and t-cell fate by injury-associated endogenous signals. Crit Rev. Immunol. 2009, 29 (1), 69−86. (26) Serhan, C. N. Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol. Aspects Med. 2017, 58, 1−11. (27) Strebovsky, J.; Walker, P.; Dalpke, A. H. Suppressor of cytokine signaling proteins as regulators of innate immune signaling. Front. Biosci., Landmark Ed. 2012, 17, 1627−1639. (28) Cain, D. W.; Cidlowski, J. A. Specificity and sensitivity of glucocorticoid signaling in health and disease. Best Pract Res. Clin Endocrinol Metab. 2015, 29 (4), 545−556. (29) Huston, J. M. The vagus nerve and the inflammatory reflex: Wandering on a new treatment paradigm for systemic inflammation and sepsis. Surg Infect (Larchmt) 2012, 13 (4), 187−193. (30) Chen, W.; Ma, X.; Zhang, P.; Li, Q.; Liang, X.; Liu, J. Mir-2123p inhibits lps-induced inflammatory response through targeting hmgb1 in murine macrophages. Exp. Cell Res. 2017, 350 (2), 318−326. (31) Zhang, L.; Wang, Y.; Ma, J.; Lai, X.; Fang, J.; Li, G.; Xu, L.; Pan, G.; Chen, Z. Exogenous mscs ameliorate hypoxia/reoxygenation injury in renal tubular epithelial cells through jak/stat signaling pathway-
PRR, pattern recognition receptor; V(D)J, variable (diversity) joining; CXCL-12, C-X-C motif ligand 12; CXCR4, C-X-C motif receptor 4; RAGE, receptor for advanced glycation endproducts; dsRNA, double-stranded RNA; NET, neutrophil extracellular trap; SAA, serum amyloid A; IL-6, interleukin 6; MIP, macrophage inflammatory protein; miRNA, microRNA; SOCS, suppressor of cytokine signaling; HPA, hypothalamic− pituitary axis; CAP, cholinergic anti-inflammatory pathway; PTM, post-translational modification; CD-24, cluster of designation 24; Mac-1, macrophage-1 antigen; TRP, transient receptor potential; SPR, surface plasmon resonance; Mtx, methotrexate; EMSA, electromobility-shift assay; ICM, inflachromene; siRNA, short-interfering RNA; NLS, nuclearlocalization sequence; CLP, cecal-ligation and puncture; SA, salicylic acid; 3-AE-SA, 3-aminoethylsalicylic acid; Kd, dissociation constant; MD-2, myeloid differentiation factor 2; EGCG, epigallocatechin 3-gallate; gapdh, glyceraldehyde 3-phosphate dehydrogenase; AMPK, AMP-activated protein kinase; CD-14, cluster of designation 14; EAE, experimental autoimmune encephalomyelitis; sRAGE, soluble receptor for advanced glycation endproducts; OA, osteoarthritis; JIA, juvenile idiopathic arthritis; RA, rheumatoid arthritis; CAD, coronary artery disease; PAH, pulmonary arterial hypertension; CHD, coronary heart disease; ALI, acute lung injury; ICU, intensive care unit; UC, ulcerative colitis; CD, Crohn’s disease; AKI, acute kidney injury; CKD, chronic kidney disease; ALF, acute liver failure; SIRS, systemic inflammatory response syndrome; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SOFA, sequential organ failure assessment; DIC, disseminated intravascular coagulation; FDA, Food and Drug Administration
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