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.
References
Aug 15, 1996·Nature·T NagasawaT Kishimoto
Jan 14, 1998·Nature Medicine·G A DonzellaJ P Moore
May 16, 1998·Current Biology : CB·N HevekerJ Schneider-Mergener
May 29, 2000·The Journal of Biological Chemistry·A BrelotM Alizon
Jul 18, 2001·The Journal of General Virology·T Dragic
Sep 12, 2001·The Journal of Biological Chemistry·N ZhouZ Huang
Oct 31, 2001·Antiviral Research·Cecilia CabreraJosé A Esté
Dec 19, 2001·Biochemistry·A LitovchickG Borkow
Mar 30, 2002·The Journal of Biological Chemistry·Wen-Bo ZhangStephen C Peiper
Apr 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Tetsuji OkadaYoshinori Shichida
Sep 5, 2002·Nature Reviews. Drug Discovery·Andrew L Hopkins, Colin R Groom
Oct 3, 2002·Leukemia·T Lapidot, O Kollet
Sep 6, 2003·The Journal of Biological Chemistry·John O TrentStephen C Peiper
Dec 4, 2003·Journal of Computational Chemistry·Holger Gohlke, David A Case
May 27, 2004·Proteins·Alexander BerchanskiMiriam Eisenstein
Jul 13, 2004·Reviews in Medical Virology·Theodore C PiersonStefan Pöhlmann
Jan 15, 2005·Journal of Virology·Xavier CarnecTatjana Dragic
Mar 22, 2005·Current Drug Targets. Infectious Disorders·G Borkow, A Lapidot
Sep 20, 2005·Nature Immunology·Ayelet DarTsvee Lapidot
Jun 15, 2007·Biochimica Et Biophysica Acta·Alexander Berchanski, Aviva Lapidot
Nov 22, 2007·The FEBS Journal·Ravi HegdeAviva Lapidot
Citations
Dec 6, 2008·Journal of Molecular Modeling·Alexander Berchanski, Aviva Lapidot
Feb 10, 2012·International Journal of Peptides·Shawn KeoganFred C Krebs
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
Sep 23, 2008·The FEBS Journal·Aviva LapidotGadi Borkow
Jun 10, 2011·The FEBS Journal·Andy ChevignéSabrina Deroo
Aug 26, 2021·Retrovirology·E A Nickoloff-BybelP J Gaskill