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Table 1. mCD4-HS12 antiviral activity in PBMCThis molecule is conceptually distinct from any other existing ones, displays low nMaffinity for gp120, and inhibits the binding of HIV-1 to cell surface CD4, CCR5, CXCR4and HS, the major ligands involved in virus attachment and entry. This innovativecompound, which displays strong anti viral activity (IC 50 2 to 5 nM) is the first moleculetargeting the coreceptor binding site of gp120. A remarkable characteristic of mCD4-HS 12is its ability to neutralize HIV-1 in a coreceptor independent manner (inhibition of CCR5-,CXCR4- and dual- tropic HIV-1 stains). This is a significant advantage since the efficacyof CCR5-specific antagonists could be jeopardized by the emergence of more aggressiveviral strains that utilize CXCR4 and for which no inhibitors are yet available. Thismolecule, acting very early in the viral life cycle, has potential for both prevention andtherapy following topical and/or parenteral application.Ongoing work is on simplifying the HS part of the molecule. Indeed, a conjugatecontaining an acidic peptide, mCD4-GPR1, still displays nanomolar antiviral activity(200nM). HS12 replacement by heparin mimic peptides is under investigation, as well asmore general replacement by polyanionic compounds.AcknowledgmentsThis work was supported by ANRS agency.References1. Vives, R.R., Imberty, A., Sattentau, Q.J., Lortat-Jacob, H. J. Biol. Chem. 280, 21353-21357 (2005).2. Crublet, E., Andrieu, J.P., Vives, R.R., Lortat-Jacob, H. J. Biol. Chem. 283, 15193-15200 (2008).3. Baleux, F., Loureiro-Morais, L., Hersant, Y., Clayette, P., Arenzana-Seisdedos, F., Bonnaffe, D.,Lortat-Jacob, H. Nat. Chem. Biol. 5, 743-748 (2009).4. Huang, C.C., Stricher, F., Martin, L., Decker, J.M., Majeed, S., Barthe, P., Hendrickson, W.A.,Robinson, J., Roumestand, C., Sodroski, J., Wyatt, R., Shaw, G.M., Vita, C., Kwong, P.D. Structure13, 755-768 (2005).39