title: Polyvalent side chain peptide-synthetic polymer conjugates as HIV-1 entry inhibitors.
abstract: This report describes the synthesis and properties of a series of polyvalent side chain peptide-synthetic polymer conjugates designed to block the CD4 binding site on gp120 and inhibit HIV-1 entry into a host cell. The peptide sequences in the conjugates are based on the CDR H3 region of the neutralizing anti-HIV-1 antibody IgG1 b12. Using a consecutive ester-amide/thiol-ene postpolymerization modification strategy, a library of polymer conjugates was prepared. Evaluation of the HIV-1 inhibitory properties revealed that midsized polymer conjugates displayed the highest antiviral activity, while shorter and longer conjugates proved to be less efficacious inhibitors. The lower molecular weight conjugates may not have sufficient length to span the distance between two neighboring gp120 containing spikes, while the higher molecular weight conjugates may be compromised due to a higher entropic penalty that would accompany their binding to the viral envelope. Although the IC(50) values for these polymer conjugates are higher than that of the parent IgG1 b12 antibody, the strategy presented here may represent an interesting antiviral approach due to the attractive properties of such polymer therapeutics (relatively inexpensive production and purification costs, high thermal and chemical stability in storage conditions, long half-life in biological tissues, low immunogenicity, and protection from proteolytic degradation).
authors.affiliation: Institut des Matériaux and Institut des Sciences et Ingénierie Chimiques, Laboratoire des Polymères, École Polytechnique Fédérale de Lausanne (EPFL), Bâtiment MXD, Station 12, CH-1015 Lausanne, Switzerland.
authors.forename: Maarten
authors.initials: M
authors.lastname: Danial
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Root
authors.forename: Harm-Anton
authors.initials: HA
authors.lastname: Klok
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000737:chemistry; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D010455:Peptides; D011108:Polymers; C514793:gp120 protein, Human immunodeficiency virus 1