Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors

Jiang, Xiangyi; Wu, Gaochan; Zalloum, Waleed A.; Meuser, Megan E.; Dick, Alexej; Sun, Lin; Chen, Chin Ho; Kang, Dongwei; Jing, Lanlan; Jia, Ruifang; Simon, Chantal; Lee, Kuo‐Hsiung; Liu, Xinyong; Zhan, Peng

doi:10.1039/c9ra05869a

Cited by 47 publications

(35 citation statements)

References 42 publications

(36 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

“…These inhibitors show that exploiting the structure and function of the CA protein is a viable therapeutic avenue to prevent HIV-1 infection and have led numerous research groups to further explore analogs of these compounds with similar binding sites and functional mechanisms [ 32 , 33 , 34 , 152 , 153 , 154 , 162 , 163 , 164 , 165 , 166 , 167 ].…”

Section: Hiv-1 Ca As a Target For Inhibitorsmentioning

confidence: 99%

Structure, Function, and Interactions of the HIV-1 Capsid Protein

Rossi

Meuser

Cunanan

et al. 2021

Life

Self Cite

View full text Add to dashboard Cite

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

show abstract

“…Very recently, screens for HIV-1 CA inhibitors have led to the discovery of 6a-9, one of a series of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives with antiviral activity similar to that of PF74 [ 124 , 136 ]. Additionally, a screen for natural products that bind to the CA-CTD yielded two linear diarylheptanoids, rubranol and hirsutanonol, that bind to the CA-CTD and allosterically inhibit CA assembly in vitro [ 137 ].…”

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

Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors

Abstract: Novel phenylalanine derivatives were discovered as HIV-1 capsid protein inhibitors via “click reaction”. Most of them exhibited remarkable anti-HIV-1 activity.

Cited by 47 publications

References 42 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

Structure, Function, and Interactions of the HIV-1 Capsid Protein

HIV-1 Maturation: Lessons Learned from Inhibitors

Contact Info

Product

Resources

About