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We present the design, synthesis, anti-HIV-1 and mode of action of neomy-cin 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. | ỊFEBS Journal Structure-function relationship of novel X4 HIV-1 entry inhibitors - L- and D-arginine peptide-aminoglycoside conjugates Ravi Hegde Gadi Borkow Alexander Berchanski and Aviva Lapidot Department of Organic Chemistry The Weizmann Institute of Science Rehovot Israel Keywords drug design HIV-1 entry inhibitors poly arginine-aminoglycoside conjugates structure-function relationship Correspondence A. Lapidot Department of Organic Chemistry The Weizmann Institute of Science Rehovot 76100 Israel Fax 972 8 9344142 Tel 972 8 9343413 E-mail aviva.lapidot@weizmann.ac.il Received 29 August 2007 revised 18 October 2007 accepted 29 October 2007 doi 10.1111 j.1742-4658.2007.06169.x 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 1a SDF-1a 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. Significant advances in understanding the process by which HIV-1 enters the host cells have been the focus of considerable interest owing
