title: Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule: the HIV-1 CD4:gp120 paradigm.
abstract: Rational conversion of noncontinuous active regions of proteins into a small orally bioavailable molecule is crucial for the discovery of new drugs based on inhibition of protein-protein interactions. We developed a method that utilizes backbone cyclization as an intermediate step for conversion of the CD4 noncontinuous active region into small macrocyclic molecules. We demonstrate that this method is feasible by preparing small inhibitor for human immunodeficiency virus infection. The lead compound, CG-1, proved orally available in the rat model.
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Mattan
authors.initials: M
authors.lastname: Hurevich
authors.forename: Avi
authors.initials: A
authors.lastname: Swed
authors.forename: Salim
authors.initials: S
authors.lastname: Joubran
authors.forename: Shira
authors.initials: S
authors.lastname: Cohen
authors.forename: Noam S
authors.initials: NS
authors.lastname: Freeman
authors.forename: Elena
authors.initials: E
authors.lastname: Britan-Rosich
authors.forename: Laurence
authors.initials: L
authors.lastname: Briant-Longuet
authors.forename: Martine
authors.initials: M
authors.lastname: Bardy
authors.forename: Christian
authors.initials: C
authors.lastname: Devaux
authors.forename: Moshe
authors.initials: M
authors.lastname: Kotler
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D047028:Macrocyclic Compounds; C514793:gp120 protein, Human immunodeficiency virus 1