Dimerization inhibitors of HIV-1 protease based on a bicyclic guanidinium subunit.
J Med Chem
; 46(24): 5196-207, 2003 Nov 20.
Article
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| MEDLINE
| ID: mdl-14613322
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteasa del VIH
/
Inhibidores de la Proteasa del VIH
/
Compuestos Bicíclicos Heterocíclicos con Puentes
/
Guanidinas
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2003
Tipo del documento:
Article
País de afiliación:
España