title: Structure-activity relationship of neomycin, paromomycin, and neamine-arginine conjugates, targeting HIV-1 gp120-CXCR4 binding step.
abstract: We have recently designed and synthesized aminoglycoside-arginine conjugates (AACs) as potential anti-HIV-1 agents. AACs exert a number of activities related to Tat antagonism. We here present a new set of AACs, conjugates of neomycin B, paromomycin, and neamine with different number of arginines (1-6), their (a) uptake by human T-cell lines, (b) antiviral activities, (c) competition with monoclonal antibody (mAb) 12G5 binding to CXCR4, (d) competition with stromal cell-derived factor-1 (SDF-1alpha) binding to CXCR4, and (e) competition with HIV-1 coat protein gp120 cell penetration. The appearance of mutations in HIV-1 gp120 gene in AACs resistant HIV-1 isolates, supports that AACs inhibit HIV-1 infectivity via interference of gp120-CXCR4 interaction. Our results point that the most potent AACs is the hexa-arginine-neomycin conjugate, the other multi-arginine-aminoglycoside conjugates are less active, and the mono-arginine conjugates display the lowest activity. Our studies demonstrate that, in addition to the core, the number of arginines attached to a specific aminoglycoside, are also important in the design of potent anti-HIV agents. The AACs play an important role, not only as HIV-1 RNA binders but also as inhibitors of viral entry into human cells.
authors.affiliation: Department of Organic Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Gadi
authors.initials: G
authors.lastname: Borkow
authors.forename: Veerappan
authors.initials: V
authors.lastname: Vijayabaskar
authors.forename: Humberto Herman
authors.initials: HH
authors.lastname: Lara
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Aviva
authors.initials: A
authors.lastname: Lapidot
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001120:Arginine; D002460:Cell Line; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics; D005601:Framycetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009355:Neomycin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010303:Paromomycin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; C444521:neomycin B-arginine conjugate NeoR; D005601:Framycetin; D010303:Paromomycin; D001120:Arginine; D009355:Neomycin