Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules

Vernekar, Sanjeev Kumar V.; Sahani, Rajkumar Lalji; Casey, Mary C.; Kankanala, Jayakanth; Wang, Lei; Kirby, Karen A.; Du, Haijuan; Zhang, Huanchun; Tedbury, Philip R.; Xie, Jiashu; Sarafianos, Stefan G.; Wang, Zhengqiang

doi:10.3390/v12040452

Cited by 20 publications

(29 citation statements)

References 56 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This screening served to identify some candidates with useful binding affinity, including MKN-1 ( 1 ), whose London dG value, ligand efficiency, topological polar surface area (TPSA) and SlogP value are −9.134 kcal/mol, 0.2559, 69.73 Å 2 and 4.022, respectively. The structure of MKN-1 ( 1 ) is completely different from that of known small compounds, which were previously developed [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ].…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins

et al. 2021

View full text Add to dashboard Cite

The capsid of human immunodeficiency virus type 1 (HIV-1) is a shell that encloses viral RNA and is highly conserved among many strains of the virus. It forms a conical structure by assembling oligomers of capsid (CA) proteins. CA dysfunction is expected to be an important target of suppression of HIV-1 replication, and it is important to understand a new mechanism that could lead to the CA dysfunction. A drug targeting CA however, has not been developed to date. Hydrophobic interactions between two CA molecules via Trp184/Met185 in CA were recently reported to be important for stabilization of the multimeric structure of CA. In the present study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site, was synthesized and its significant anti-HIV-1 activity was confirmed. Structure activity relationship (SAR) studies of its derivatives were performed and provided results that are expected to be useful in the future design and development of novel anti-HIV agents targeting CA.

show abstract

Section: Resultsmentioning

confidence: 99%

Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Although PF74 has been a valuable probe for studying post-entry events, its antiviral potency is relatively low and it exhibits extremely poor metabolic stability [ 122 ]. Recent studies addressing these issues have resulted in the development of modified compounds with improved potency and metabolic stability [ 123 , 124 ]. Compounds developed by Gilead Sciences based on the PF74 scaffold have shown tremendous therapeutic potential and are currently performing well in initial human clinical trials [ 71 , 125 ].…”

Section: Targeting Ca To Disrupt Capsid Assembly and Stabilitymentioning

confidence: 99%

HIV-1 Maturation: Lessons Learned from Inhibitors

Kleinpeter

Freed

2020

Viruses

View full text Add to dashboard Cite

Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity.

show abstract

“…PF74 has a 50% effectiveness concentration (EC 50 ) of 1.239 ± 0.257 μM and a 50% cytotoxicity concentration (CC 50 ) of 32.2 ± 9.3 μM [ 110 ]. Unfortunately, its low metabolic stability [ 111 , 112 , 113 , 114 , 115 ] makes it unsuitable for further development into a therapeutic, and as such there have been ongoing medicinal chemistry efforts to generate analogues with balanced potency and metabolic stability [ 111 , 112 , 113 , 114 ].…”

Section: Structural Insights Into the Effects Of Small Moleculesmentioning

confidence: 99%

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Wilbourne

Zhang

2021

Viruses

View full text Add to dashboard Cite

Understanding of the construction and function of the HIV capsid has advanced considerably in the last decade. This is due in large part to the development of more sophisticated structural techniques, particularly cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). The capsid is known to be a pleomorphic fullerene cone comprised of capsid protein monomers arranged into 200–250 hexamers and 12 pentamers. The latter of these induce high curvature necessary to close the cone at both ends. CryoEM/cryoET, NMR, and X-ray crystallography have collectively described these interactions to atomic or near-atomic resolutions. Further, these techniques have helped to clarify the role the HIV capsid plays in several parts of the viral life cycle, from reverse transcription to nuclear entry and integration into the host chromosome. This includes visualizing the capsid bound to host factors. Multiple proteins have been shown to interact with the capsid. Cyclophilin A, nucleoporins, and CPSF6 promote viral infectivity, while MxB and Trim5α diminish the viral infectivity. Finally, structural insights into the intra- and intermolecular interactions that govern capsid function have enabled development of small molecules, peptides, and truncated proteins to disrupt or stabilize the capsid to inhibit HIV replication. The most promising of these, GS6207, is now in clinical trial.

show abstract

Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules

Cited by 20 publications

References 56 publications

Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins

Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins

HIV-1 Maturation: Lessons Learned from Inhibitors

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Contact Info

Product

Resources

About