[A study of anti-HIV compounds which interfere the virus entry via coreceptor CXCR4].
T22 is an anti-HIV polypeptide which was synthesized with chemical modification from the horse shoe hemocytic polypeptides, polyphemusin II as a lead compound. T22 was found to block T-tropic HIV-1 entry into target cells as a CXCR4 antagonist. We synthesized T134, a small sized analog of T22 with reduced positive charges. T134 exhibited highly potent activity and significantly less cytotoxicity when compared to T22. It was shown that bicyclam AMD3100 and ALX40-4C are antagonists of CXCR4, and vMIP II which is coded chemokine in HHV8/KSHV effects antagonistically both CXCR4 and CCR5. We examined the anti-HIV activity of these CXCR4 antagonists. All of them inhibit the binding of anti-CXCR4 antibody (12G5) to PBMC, but have no effect on the binding of anti-CCR5 antibody (2D7) except for vMIP II. vMIP II decreased the binding of both 12G5 and 2D7. In these compounds, T134 showed the most potency to anti-HIV activity. We also attempted to clarify the cross resistance between these antagonists, using HIV-1 resistant to AMD3100. T134, ALX40-4C and vMIP II are active against the AMD3100 resistant strain. This observation indicates the potential of using these the inhibitors as a new type of agent preventing HIV entry.
Kanbara
K
K
Department of Microbiology and Immunology, Kagoshima University Dental School.
Fujii
N
N
Nakashima
H
H
D019380:Anti-HIV Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D003429:Cross Reactions; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000187:drug effects*
D019380:Anti-HIV Agents; D023181:Antimicrobial Cationic Peptides; D009842:Oligopeptides; D010455:Peptides; D019718:Receptors, CXCR4; C116978:T134 peptide; C076963:T22 protein, synthetic