Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly

Fader, L. D.; Bethell, Richard C.; Bonneau, Pierre; Bös, Michael; Bousquet, Yves; Cordingley, Michael G.; Coulombe, René; DeRoy, Patrick; Faucher, Anne‐Marie; Gagnon, Alexandre; Goudreau, Nathalie; Grand‐Maître, Chantal; Guse, Ingrid; Hucke, Oliver; Kawai, Stephen H.; Lacoste, Jean‐Eric; Landry, Serge; Lemke, Christopher T.; Malenfant, Éric; Mason, Stephen W.; Morin, Sébastien; O'Meara, Jeff A.; Simoneau, Bruno; Titolo, Steve; Yoakim, Christiane

doi:10.1016/j.bmcl.2010.10.131

Cited by 96 publications

(69 citation statements)

References 13 publications

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“…The notion that nonstructural proteins may be involved in virus assembly has been demonstrated in related viruses (21,24,37,39) and, therefore, warrants further investigation in the case of HCV. Inhibition of virus assembly is currently being considered an alternative therapeutic strategy for other viruses such as HIV (7,9,18,45). Therefore, a finite protein-protein interaction that is essential to infectious virion production, such as the one described here, may represent an attractive target for the development of future HCV therapies.…”

Section: Discussionmentioning

confidence: 99%

A Genetic Interaction between the Core and NS3 Proteins of Hepatitis C Virus Is Essential for Production of Infectious Virus

Jones

Atoom

Zhang

et al. 2011

J Virol

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By analogy to other members of the Flaviviridae family, the hepatitis C virus (HCV) core protein is presumed to oligomerize to form the viral nucleocapsid, which encloses the single-stranded RNA genome. Core protein is directed to lipid droplets (LDs) by domain 2 (D2) of the protein, and this process is critical for virus production. Domain 1 (D1) of core is also important for infectious particle morphogenesis, although its precise contribution to this process is poorly understood. In this study, we mutated amino acids 64 to 75 within D1 of core and examined the ability of these mutants to produce infectious virus. We found that residues 64 to 66 are critical for generation of infectious progeny, whereas 67 to 75 were dispensable for this process. Further investigation of the defective 64 to 66 mutant (termed JFH1 T -64-66) revealed it to be incapable of producing infectious intracellular virions, suggesting a fault during HCV assembly. Furthermore, isopycnic gradient analyses revealed that JFH1 T -64-66 assembled dense intracellular species of core, presumably representing nucleocapsids. Thus, amino acids 64 to 66 are seemingly not involved in core oligomerization/nucleocapsid assembly. Passaging of JFH1 T -64-66 led to the emergence of a single compensatory mutation (K1302R) within the helicase domain of NS3 that completely rescued its ability to produce infectious virus. Importantly, the same NS3 mutation abrogated virus production in the context of wild-type core protein. Together, our results suggest that residues 64 to 66 of core D1 form a highly specific interaction with the NS3 helicase that is essential for the generation of infectious HCV particles at a stage downstream of nucleocapsid assembly.Hepatitis C virus (HCV) typically establishes chronic infections of the liver that frequently lead to severe pathologies, including cirrhosis and hepatocellular carcinoma. The current combination therapy of pegylated alpha interferon (IFN-␣) and ribavirin is only partially effective and is associated with numerous side effects. Treatment for HCV is currently transitioning to the use of direct-acting antiviral (DAA) therapy, which has been specifically designed to target viral proteins essential for HCV replication (30). While early results indicate that DAA compounds show promise, a wider range of treatments targeting multiple aspects of the viral life cycle would offer improved therapeutic options to infected individuals. In this regard, a better understanding of HCV assembly could provide an alternate exploitable target.

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Section: Discussionmentioning

confidence: 99%

A Genetic Interaction between the Core and NS3 Proteins of Hepatitis C Virus Is Essential for Production of Infectious Virus

Jones

Atoom

Zhang

et al. 2011

J Virol

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“…For instance, the benzodiazepine (BD) and the benzimidazole (BM) series were reported to inhibit virion release or prevent virus maturation, respectively (61,62). In the case of the BD series, molecular studies, complemented by nuclear magnetic resonance and crystallography approaches, have shown that compounds from this class inhibited HIV particle release by blocking assembly of immature capsids (63).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

Scaturro

Trist

Paul

et al. 2014

J Virol

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Dengue viruses (DV) represent a significant global health burden, with up to 400 million infections every year and around 500,000 infected individuals developing life-threatening disease. In spite of attempts to develop vaccine candidates and antiviral drugs, there is a lack of approved therapeutics for the treatment of DV infection. We have previously reported the identification of ST-148, a small-molecule inhibitor exhibiting broad and potent antiviral activity against DV in vitro and in vivo (C. M. Byrd et al., Antimicrob. Agents Chemother. 57:15-25, 2013, doi:10.1128/AAC.01429-12). In the present study, we investigated the mode of action of this promising compound by using a combination of biochemical, virological, and imaging-based techniques. We confirmed that ST-148 targets the capsid protein and obtained evidence of bimodal antiviral activity affecting both assembly/ release and entry of infectious DV particles. Importantly, by using a robust bioluminescence resonance energy transfer-based assay, we observed an ST-148-dependent increase of capsid self-interaction. These results were corroborated by molecular modeling studies that also revealed a plausible model for compound binding to capsid protein and inhibition by a distinct resistance mutation. These results suggest that ST-148-enhanced capsid protein self-interaction perturbs assembly and disassembly of DV nucleocapsids, probably by inducing structural rigidity. Thus, as previously reported for other enveloped viruses, stabilization of capsid protein structure is an attractive therapeutic concept that also is applicable to flaviviruses. Dengue virus (DV) belongs to the genus Flavivirus, a large group of emerging pathogens capable of causing severe human diseases. Among these, DV represents the most prevalent mosquito-borne human-pathogenic virus worldwide, comprising 4 serotypes that are transmitted mainly by infected Aedes mosquitoes during a blood meal. DV infections can lead to a wide range of clinical manifestations, ranging from asymptomatic infections to life-threatening dengue hemorrhagic fever and shock syndrome. A recent study estimated around 390 million DV infections each year, resulting in approximately 100 million symptomatic cases and around 25,000 deaths (1). Despite intense efforts and growing public interest, no licensed antiviral drug against DV infection is available, and the most advanced DV vaccine candidate did not meet expectations in a recent large clinical trial (2).DV has a single-stranded RNA genome of positive polarity that codes for a polyprotein, which is co-and posttranslationally processed into three structural proteins (capsid, prM, and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3). The virus enters mammalian cells via receptor-mediated endocytosis. In the endosomal compartment, the low pH induces a conformational change in the envelope (E) protein, triggering membrane fusion and nucleocapsid release into the cytoplasm (4, 5). Disassembly of the nucleocapsid occur...

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“…145 Optimization of the benzodiazepine series led to a compound with significantly improved potency. 146 Together, these studies indicate that HIV-1 CA is a potential drug target.…”

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confidence: 99%

HIV Type 1 Gag as a Target for Antiviral Therapy

Waheed

Freed

2012

AIDS Research and Human Retroviruses

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The Gag proteins of HIV-1 are central players in virus particle assembly, release, and maturation, and also function in the establishment of a productive infection. Despite their importance throughout the replication cycle, there are currently no approved antiretroviral therapies that target the Gag precursor protein or any of the mature Gag proteins. Recent progress in understanding the structural and cell biology of HIV-1 Gag function has revealed a number of potential Gag-related targets for possible therapeutic intervention. In this review, we summarize our current understanding of HIV-1 Gag and suggest some approaches for the development of novel antiretroviral agents that target Gag.

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Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly

Cited by 96 publications

References 13 publications

A Genetic Interaction between the Core and NS3 Proteins of Hepatitis C Virus Is Essential for Production of Infectious Virus

A Genetic Interaction between the Core and NS3 Proteins of Hepatitis C Virus Is Essential for Production of Infectious Virus

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

HIV Type 1 Gag as a Target for Antiviral Therapy

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