title: Dimerization inhibitors of HIV-1 protease based on a bicyclic guanidinium subunit.
abstract: Original inhibitors of HIV-1 protease based on a chiral bicyclic guanidinium scaffold linked to short peptidic mimics of the terminal protease sequences and to a lipophilic group were designed. These inhibitors prevent dimerization of the native protease by an interfacial structure at the highly conserved antiparallel beta-strand involving both the N and C termini that substantially account for dimerization. The preorganized guanidinium spacer introduces additional electrostatic hydrogen-bonding interactions with the C-terminal Phe-99 carboxylate. Lipophilic residues linked to side chains and the guanidinium scaffold are essential for dimerization inhibition as ascertained by Zhang kinetics (4, K(id) = 290 nM; 6 or 6', K(id) = 150 nM; 8, K(id) = 400 nM) combined with a circular dichroism study on the enzyme thermal stability. Remarkably, less hydrophobic compounds result in mixed dimerization (1a and 3) or active site inhibitors (5). Removal of the guanidinium hydrophobic groups leads to less active or inactive ligands.
authors: Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors: Perla
authors: P
authors: Breccia
authors: Nicole
authors: N
authors: Boggetto
authors: Ruth
authors: R
authors: Pérez-Fernández
authors: Michiel
authors: M
authors: Van Gool
authors: Masayuki
authors: M
authors: Takahashi
authors: Loïc
authors: L
authors: René
authors: Pilar
authors: P
authors: Prados
authors: Bernard
authors: B
authors: Badet
authors: Michèle
authors: M
authors: Reboud-Ravaux
authors: Javier
authors: J
authors: de Mendoza
mesh_terms: D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D002942:Circular Dichroism; D019281:Dimerization; D006146:Guanidines / Q000737:chemistry*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D012694:Serine / Q000737:chemistry; D013237:Stereoisomerism; D014443:Tyrosine / Q000737:chemistry
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D006146:Guanidines; D017320:HIV Protease Inhibitors; D014443:Tyrosine; D012694:Serine; D016333:HIV Protease