title: Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site.
abstract: Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR. Synthesis of the new derivatives, the effect of substituents at the C-28 position and their hydrosolubility are discussed. The ability of these molecules to inhibit viral infection and their cytotoxicity is assessed. Compared to the well-known bevirimat (2), one of our compounds (16) shows a higher hydrosolubility associated with a 2.5 fold increase in activity, a higher selectivity index and a better antiviral profile. Moreover, for the first time a direct interaction between a derivative of bevirimat (16) and the domain CA-SP1-NC is shown by NMR. Information from this study should allow us to decipher the mechanism by which bevirimat inhibits HIV-1 maturation and how the natural polymorphism of the spacer peptide SP1 triggers resistance to inhibitors.
authors: Université Paris Descartes, Sorbonne Paris Cité, Laboratoire de Cristallographie et RMN Biologiques, UMR 8015 CNRS, 4 av. de l'Observatoire, Paris, France.
authors: Pascale
authors: P
authors: Coric
authors: Serge
authors: S
authors: Turcaud
authors: Florence
authors: F
authors: Souquet
authors: Laurence
authors: L
authors: Briant
authors: Bernard
authors: B
authors: Gay
authors: Jacques
authors: J
authors: Royer
authors: Nathalie
authors: N
authors: Chazal
authors: Serge
authors: S
authors: Bouaziz
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*; D053978:Pentacyclic Triterpenes
chemical_list: D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C479935:bevirimat; D053978:Pentacyclic Triterpenes