A synthetic CD4-heparan sulfate glycoconjugate inhibits CCR5 and CXCR4 HIV-1 attachment and entry.
The HIV-1 envelope, gp120, which features the binding determinants for both CD4 and coreceptor recognition, is key for virus entry and represents an attractive pharmacological target. However, critical domains for entry (coreceptor and CD4 binding sites) are either cryptic or located in partially occluded cavities. Here we developed a chemical approach to synthesize a CD4-mimetic peptide linked to a heparan sulfate dodecasaccharide. This molecule binds to gp120, induces the exposure of the coreceptor binding domain and renders it available for interaction with the oligosaccharide. The linkage between the CD4 mimetic and the heparan sulfate derivative provides strong cooperative effects, resulting in low-nanomolar antiviral activity toward both CCR5- and CXCR4-tropic HIV-1 strains. This compound, which has the unique ability to simultaneously target two critical and highly conserved regions of gp120, establishes a new type of inhibitor and suggests a general concept for the inhibition of numerous other biological systems.
Baleux
Françoise
F
Unité de Chimie des Biomolécules, Institut Pasteur, Centre National de la Recherche Scientifique 2128, Paris, France.
Loureiro-Morais
Latino
L
Hersant
Yael
Y
Clayette
Pascal
P
Arenzana-Seisdedos
Fernando
F
Bonnaffé
David
D
Lortat-Jacob
Hugues
H
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000494:pharmacology*; D006001:Glycoconjugates / Q000737:chemistry / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008958:Models, Molecular; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D053585:Virus Attachment / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects*
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D006001:Glycoconjugates; D015699:HIV Envelope Protein gp120; D006497:Heparan Sulfate; D019713:Receptors, CCR5; D019718:Receptors, CXCR4