Identification of novel small molecule CXCR4 inhibitors as anti-HIV agents

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	STRUCTBIO-1

Authors

• D. Das
• K. Maeda
• Y. Hayashi
• N. Gavande
• D. V. Desai
• S.B. Chang
• A.K. Ghosh
• H. Mitsuya

Abstract

The HIV envelope glycoprotein gp120 interacts with either CXCR4 or CCR5 for viral entry into cells and subsequent infection. We carried out a computational search of a large chemical library to identify small molecules that potentially bind to CXCR4, inhibit the fusion with gp120 and demonstrate anti-HIV activity. The computational search initially identified molecules that have a high shape similarity to a known small molecule inhibitor of HIV. These molecules were subsequently docked into the crystal structure of CXCR4. We analyzed the docked poses to select sixteen molecules for biological assays. Our assays identified three compounds, all piperidine substituents, that inhibit the interaction of CXCR4 with its natural ligand SDF-1α. The most promising analogue inhibits the interaction of SDF-1α with CXCR4 with an IC50 of 48 nM, and has an anti-HIV activity of 400 nM. Structural modeling suggests that the compounds exert their binding and antiviral activity through interactions with D97 and/or E288, which are located in transmembranes 2 and 7 of CXCR4. Ca2+-flux assays suggest that the identified molecules are antagonists of CXCR4. The combination of chemokine inhibition, Ca2+-flux and antiviral assays demonstrate that the piperidine analogues are novel anti-HIV inhibitors that selectively target CXCR4.

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