title: NeoR6 inhibits HIV-1-CXCR4 interaction without affecting CXCL12 chemotaxis activity.
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.
authors.affiliation: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. aviva.lapidot@weizmann.ac.il
authors.forename: Aviva
authors.initials: A
authors.lastname: Lapidot
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.forename: Alexander
authors.initials: A
authors.lastname: Berchanski
authors.forename: Boaz
authors.initials: B
authors.lastname: Pal
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
authors.forename: Gadi
authors.initials: G
authors.lastname: Borkow
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects*; D000080027:Cyclams; D005786:Gene Expression Regulation / Q000187:drug effects; D015497:HIV-1 / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D009355:Neomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; C530384:NeoR6 compound; D009842:Oligopeptides; D019718:Receptors, CXCR4; D001120:Arginine; C116977:T140 peptide; D009355:Neomycin; C088327:plerixafor