Structure-function relationship of novel X4 HIV-1 entry inhibitors - L- and D-arginine peptide-aminoglycoside conjugates.
We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers D- and L-arginine peptides (APACs). The d-APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective L-APACs. D-arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their L-arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1alpha (SDF-1alpha)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. D-APACs readily concentrate in the nucleus, whereas the l-APACs do not. 9-mer-D-arginine analogues are more efficient inhibitors than the 6-mer-D-arginine conjugates and the neomycin-D-polymers are better inhibitors than their respective neamine conjugates. This and further structure-function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors.
Hegde
Ravi
R
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Borkow
Gadi
G
Berchanski
Alexander
A
Lapidot
Aviva
A
D000617:Aminoglycosides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry*; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D018613:Microscopy, Confocal; D008956:Models, Chemical; D015394:Molecular Structure; D019718:Receptors, CXCR4 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000617:Aminoglycosides; D019380:Anti-HIV Agents; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D001120:Arginine