1. Amino acid derivatives of the (-) enantiomer of gossypol are effective fusion inhibitors of human immunodeficiency virus type 1.
- Author
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An T, Ouyang W, Pan W, Guo D, Li J, Li L, Chen G, Yang J, Wu S, and Tien P
- Subjects
- Amino Acids toxicity, Cell Line, Circular Dichroism, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Gossypol toxicity, HIV Envelope Protein gp41 antagonists & inhibitors, HIV Fusion Inhibitors toxicity, HIV-1 physiology, Humans, Protein Binding, Virus Internalization drug effects, Virus Replication drug effects, Amino Acids chemistry, Amino Acids pharmacology, Gossypol analogs & derivatives, Gossypol pharmacology, HIV Fusion Inhibitors chemistry, HIV Fusion Inhibitors pharmacology, HIV-1 drug effects
- Abstract
T20 and maraviroc are the only two currently available entry inhibitors that have shown efficacy in treating HIV-1-infected individuals who have failed to respond to first-line antiretroviral drugs. Gossypol is a polyphenolic aldehyde extracted from cotton plants. By modifying the (-) enantiomer of gossypol with a series of small molecules, we have found that neutral amino acids with aliphatic group derivatives of (-) gossypol show the strongest inhibitory activity and the lowest cytotoxicity in vitro among all the derivatives tested. Additionally, the selectivity index of the (-) gossypol-neutral amino acid conjugates is increased 100-fold when compared with (-) gossypol alone. It is widely accepted that gossypol and gossypol derivatives inhibit HIV-1 replication by targeting reverse transcriptase. However, from the results of our time-of-addition assay, HIV-1-mediated cell fusion assay and VSV-G pseudotyped virus assay, we demonstrate that the alanine-(-) gossypol derivative ((-)G-Ala) is an effective HIV-1 entry inhibitor. Further mechanistic analysis revealed that (-)G-Ala neither blocks gp120-CD4 binding nor interacts with the HIV-1 co-receptor CXCR4. Results from sandwich ELISA, native-PAGE and circular dichroism (CD) show that (-)G-Ala inhibits the cell fusion-activated gp41 core domain. Moreover, (-)G-Ala binds to the HIV-5-Helix protein and blocking D-peptide (PIE7) binding to the hydrophobic pocket on the surface of the gp41 internal trimeric coiled-coil domain. The contraceptive properties of (-) gossypol and amino acid derivatives of (-) gossypol are also discussed. Collectively, our results indicate that (-)G-Ala may bind to the gp41 hydrophobic pocket and block the formation of the cell fusion-activated gp41 core to inhibit HIV-1-mediated membrane fusion and subsequent viral entry., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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