RESUMO
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.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Guanidinas/química , Inibidores da Protease de HIV/química , Protease de HIV/metabolismo , Sítios de Ligação , Dicroísmo Circular , Dimerização , Interações Hidrofóbicas e Hidrofílicas , Cinética , Modelos Moleculares , Estrutura Secundária de Proteína , Serina/química , Estereoisomerismo , Tirosina/químicaRESUMO
A general method giving access to protected alpha-alkyl amino glycines (A3G) 4 from the previously described precursor alpha-isopropylthioglycine 1 is described. In the presence of N-bromosuccinimide, displacement of the thiol by a large variety of amines afforded the corresponding racemic amino acid mimics. The efficiency of the reaction was strongly dependent on the protective groups of the nucleophile used in the condensation.