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 1α (SDF‐1α)/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.