Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes.
Curcumin, a relatively non-toxic natural product isolated from Curcuma longa, is a modest inhibitor of the HIV-1 (IC50 = 100 microM) and HIV-2 (IC50 = 250 microM) proteases. Simple modifications of the curcumin structure raise the IC50 value but complexes of the central dihydroxy groups of curcumin with boron lower the IC50 to a value as low as 6 microM. The boron complexes are also time-dependent inactivators of the HIV proteases. The increased affinity of the boron complexes may reflect binding of the orthogonal domains of the inhibitor in interesecting sites within the substrate-binding cavity of the enzyme, while activation of the alpha, beta-unsaturated carbonyl group of curcumin by chelation to boron probably accounts for time-dependent inhibition of the enzyme.
Sui
Z
Z
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
Salto
R
R
Li
J
J
Craik
C
C
Ortiz de Montellano
P R
PR
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D001895:Boron / Q000737:chemistry / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2; D003474:Curcumin; D001895:Boron