Abstract
According to the 2018 report of the United Nations Programme on HIV/AIDS (UNAIDS), acquired immune deficiency syndrome (AIDS), a disease caused by the human immunodeficiency virus (HIV), remains a significant public health problem. The non-existence of a cure or effective vaccine for the disease and the associated emergence of resistant viral strains imply an urgent need for the discovery of novel anti-HIV drug candidates. The current study aimed to identify potential anti-retroviral compounds from Alchornea cordifolia. Bioactive compounds were identified using several chromatographic and spectroscopic techniques and subsequently evaluated for cytotoxicity and anti-HIV properties. Molecular modelling studies against HIV-1 integrase (HIV-1 IN) were performed to decipher the mode of action of methylgallate, the most potent compound (IC50 = 3.7 nM) and its analogues from ZINC database. Cytotoxicity assays showed that neither the isolated compounds nor the crude methanolic extract displayed cytotoxicity effects on the HeLa cell line. A strong correlation between the in vitro and in silico results was observed and important HIV-1 IN residues interacting with the different compounds were identified. These current results indicate that methylgallate is the main anti-HIV-1 compound in A. cordifolia stem bark, and could be a potential platform for the development of new HIV-1 IN inhibitors.
Highlights
Acquired immune deficiency syndrome (AIDS), a disease caused by the human immunodeficiency virus (HIV), remains a significant public health problem with more than 76.1 million people infected since its discovery in 19811,2
The different highly active antiretroviral therapy (HAART) components suppress the replication of the virus in host cells by targeting different stages of its replication cycle: (i) viral entry; (ii) viral cDNA synthesis [reverse transcriptase (RT) inhibitors]; (iii) viral cDNA-host DNA integration [integrase (IN) inhibitors]; (iv) virion release and maturation [protease (PR) inhibitors]9
catalytic core domain (CCD) viral mutants with G148H, N155H and G148H/G140S polymorphisms have been reported and have shown resistance against Elvitegravir and Dolutegravir underscoring the need for the development of novel drugs[54,55]
Summary
Acquired immune deficiency syndrome (AIDS), a disease caused by the human immunodeficiency virus (HIV), remains a significant public health problem with more than 76.1 million people infected since its discovery in 19811,2. The HIV-1 IN enzyme is a 288-amino acid protein with three domains: N-terminal domain[18] (NTD; residues 1–49); the catalytic core domain (CCD; residues 50–212)[19] and the C-terminal domain (CTD; residues 213–288)[20] It plays an essential role in the viral replication cycle by covalently integrating pro-viral cDNA into the host cell’s chromosomal DNA via a two-step SN2 nucleophilic reaction: a 3′-end viral cDNA processing and the strand transfer reaction. As part of our effort to identify potential anti-retroviral hits, current work evaluates the HIV-1 IN inhibitory properties and cytotoxicity properties of compounds from Alchornea cordifolia stem bark using the recombinant form of the enzyme and human HeLa cells respectively. The results presented here indicate that methylgallate is the main anti-HIV-1 compound in A. cordifolia crude extract and could be a potential platform for the development of newer HIV-1 IN inhibitors
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