Abstract
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.
Highlights
Accepted: 12 January 2021As a retrovirus, human immunodeficiency virus type 1 (HIV-1) can infect CD4-positiveT-cells or macrophage, eventually causing acquired immunodeficiency syndrome (AIDS).To date, many anti-HIV-1 drugs [1,2,3], such as inhibitors of reverse transcriptase [4], protease [5] and integrase [6,7], have been developed for the therapeutic treatment of HIV-1infected individuals and AIDS patients
The side chains of these two residues were fixed in place, and the backbone structures crosslinking two side-chain functional groups were screened against the linker database provided by Molecular Operating Environment (MOE) to bind to the receptor side (Figure 2)
Two pharmacophore functional groups of MKN-1 (1), which was originally designed as a dipeptide mimic of Trp184 and Met185, are both important for high anti-HIV activity and should not be modified
Summary
Many anti-HIV-1 drugs [1,2,3], such as inhibitors of reverse transcriptase [4], protease [5] and integrase [6,7], have been developed for the therapeutic treatment of HIV-1infected individuals and AIDS patients. There are serious defects which have not been escaped These contain the appearance of mutant viral strains with multi-drug resistance, emergence of severe side effects and costs of the dosed drugs. In an effort to solve these problems and enhance the repertoire of anti-HIV-1 drugs, we have sought drugs with different mechanisms of action such as coreceptor CXCR4 antagonists [8,9,10,11,12,13,14], CD4 mimics [15,16,17,18,19], fusion inhibitors [20,21,22,23], integrase inhibitors [24,25,26] and inhibitors of viral uncoating and viral assembly [27,28,29,30]
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