The Evaluation of Statins as Potential Inhibitors of the LEDGF/p75-HIV-1 Integrase interaction

• Published in: Chemical biology & drug design 2015-03, Vol.85 (3), p.290-295
• Main Authors: Harrison, Angela T., Kriel, Frederik H., Papathanasopoulos, Maria A., Mosebi, Salerwe, Abrahams, Shaakira, Hewer, Raymond
• Format: Article
• Language: English
• Subjects: AlphaScreen; Cells, Cultured; Drug Evaluation, Preclinical; HIV Integrase - chemistry; HIV Integrase - genetics; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - enzymology; HIV-1 - physiology; HIV-1 integrase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; LEDGF/p75; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; lovastatin; Lovastatin - chemistry; Lovastatin - pharmacology; Protein Interaction Domains and Motifs - drug effects; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; statins; Virus Replication - drug effects
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12384

Lovastatin was identified through virtual screening as a potential inhibitor of the LEDGF/p75–HIV‐1 integrase interaction. In an AlphaScreen assay, lovastatin inhibited the purified recombinant protein–protein interaction (IC50 = 1.97 ± 0.45 μm) more effectively than seven other tested statins. None of the eight statins, however, yielded antiviral activity in vitro, while only pravastatin lactone yielded detectable inhibition of HIV‐1 integrase strand transfer activity (31.65% at 100 μm). A correlation between lipophilicity and increased cellular toxicity of the statins was observed. In this study, the known drug lovastatin was identified as an inhibitor of the LEDGF/p75‐ HIV‐1 integrase interaction, atorvastatin was also verified as an inhibitor of the LEDGF/p75‐IN interaction and statin lipophilicity was observed to increase cellular toxicity.