NeoR6 inhibits HIV-1-CXCR4 interaction without affecting CXCL12 chemotaxis activity.

Biochimica Et Biophysica Acta
Aviva LapidotGadi Borkow

Abstract

Aminoglycoside-arginine conjugates (AACs) are multi-target HIV-1 inhibitors. The most potent AAC is neomycin hexa-arginine conjugate, NeoR6. We here demonstrate that NeoR6 interacts with CXCR4 without affecting CXCL12-CXCR4 ordinary chemotaxis activity or loss of CXCR4 cell surface expression. Importantly, NeoR6 alone does not affect cell migration, indicating that NeoR6 interacts with CXCR4 at a distinct site that is important for HIV-1 entry and mAb 12G5 binding, but not to CXCL12 binding or signaling sites. This is further supported by our modeling studies, showing that NeoR6 and CXCL12 bind to two distinct sites on CXCR4, in contrast with other CXCR4 inhibitors, e.g. T140 and AMD3100. This complementary utilization of chemical, biology, and computation analysis provides a powerful approach for designing anti-HIV-1 drugs without interfering with the natural function of CXCL12/CXCR4 binding.

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Citations

Dec 6, 2008·Journal of Molecular Modeling·Alexander Berchanski, Aviva Lapidot
Jan 31, 2012·Expert Opinion on Investigational Drugs·Amnon PeledJan Burger
Aug 10, 2011·Biochemical Pharmacology·Andy ChevignéSabrina Deroo
Mar 31, 2009·Bioorganic & Medicinal Chemistry Letters·Yanli XuLihe Zhang
Jun 10, 2011·The FEBS Journal·Andy ChevignéSabrina Deroo
Aug 26, 2021·Retrovirology·E A Nickoloff-BybelP J Gaskill

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