Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanisms of drug action.
J Med Chem
; 40(19): 3057-63, 1997 Sep 12.
Article
en En
| MEDLINE
| ID: mdl-9301668
We have previously reported the inhibitory activity of curcumin against human immunodeficiency virus type one (HIV-1) integrase. In the present study, we have synthesized and tested analogs of curcumin to explore the structure-activity relationships and mechanism of action of this family of compounds in more detail. We found that two curcumin analogs, dicaffeoylmethane (6) and rosmarinic acid (9), inhibited both activities of integrase with IC50 values below 10 microM. We have previously demonstrated that lysine 136 may play a role in viral DNA binding. We demonstrated equivalent potencies of two curcumin analogs against both this integrase mutant and wild-type integrase, suggesting that the curcumin-binding site and the substrate-binding site may not overlap. Combining one curcumin analog with the recently described integrase inhibitor NSC 158393 resulted in integrase inhibition which was synergistic, reflective of drug-binding sites which may not overlap. We have also determined that these analogs can inhibit binding of the enzyme to the viral DNA but that this inhibition is independent of divalent metal ion. Furthermore, kinetic studies of these analogs suggest that they bind to the enzyme at a slow rate. These studies can provide mechanistic and structural information which may guide the future design of integrase inhibitors.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Catecoles
/
Inhibidores de Integrasa VIH
/
Integrasa de VIH
/
Curcumina
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1997
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos