title: Synthesis and anti-HIV activity of trivalent CD4-mimetic miniproteins.
abstract: A series of trivalent CD4-mimetic miniproteins was synthesized, in which three CD4M9 miniprotein moieties were tethered on a threefold-symmetric scaffold. The trivalent miniproteins were designed to target the CD4-binding sites displayed in the trimeric gp120 complex of HIV-1. The synthesis takes advantage of the highly efficient ligation between a cysteine-tagged CD4M9 miniprotein and a suitable trivalent maleimide that varied in the nature and length of spacer. Antiviral assay revealed that most of the synthetic trivalent miniproteins demonstrated significantly enhanced anti-HIV activities over the monomeric CD4M9 against both R5- and X4-tropic viruses, indicating the beneficial multivalent effects. One compound that possesses a hydrophobic linker was shown to be 140-fold more active than CD4M9 against HIV-1(Bal) infection, implicating a positive contribution of the lipid portion to the antiviral activity. It was also found that most of the trivalent miniproteins showed comparable anti-HIV activities in comparison with a typical bivalent miniprotein, regardless of the length of the linker. The results implicate a novel mechanism of the interactions between the multivalent inhibitors and the trimeric gp120 complex.
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Hengguang
authors.initials: H
authors.lastname: Li
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Guan
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szczepanska
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Moreno-Vargas
authors.forename: Ana T
authors.initials: AT
authors.lastname: Carmona
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Robina
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.forename: Lai-Xi
authors.initials: LX
authors.lastname: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015704:CD4 Antigens / Q000737:chemistry*; D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens