Acridone alkaloids as potent inhibitors of cathepsin V


Autoria(s): SEVERINO, Richele P.; GUIDO, Rafael Victório Carvalho; MARQUES, Emerson F.; BROEMME, Dieter; SILVA, M. Fatima das G. F. da; FERNANDES, Joao B.; ANDRICOPULO, Adriano Defini; VIEIRA, Paulo C.
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

20/10/2012

20/10/2012

2011

Resumo

Cathepsin V is a lysosomal cysteine peptidase highly expressed in thymus, testis and corneal epithelium. Eleven acridone alkaloids were isolated from Swinglea glutinosa (Bl.) Merr. (Rutaceae), with eight of them being identified as potent and reversible inhibitors of cathepsin V (IC(50) values ranging from 1.2 to 3.9 mu M). Detailed mechanistic characterization of the effects of these compounds on the cathepsin V-catalyzed reaction showed clear competitive inhibition with respect to substrate, with dissociation constants (K(i)) in the low micromolar range (2, K(i) = 1.2 mu M; 6, K(i) = 1.0 mu M; 7, K(i) = 0.2 mu M; and 11, K(i) = 1.7 mu M). Molecular modeling studies provided important insight into the structural basis for binding affinity and enzyme inhibition. Experimental and computational approaches, including biological evaluation, mode of action assessment and modeling studies were successfully employed in the discovery of a small series of acridone alkaloid derivatives as competitive inhibitors of catV. The most potent inhibitor (7) has a K(i) value of 200 nM. (C) 2011 Elsevier Ltd. All rights reserved.

State of Sao Paulo Research Foundation (FAPESP, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

National Council for Scientific and Technological Development (CNPq, Conselho Nacional de Pesquisa e Desenvolvimento), Brazil

Identificador

BIOORGANIC & MEDICINAL CHEMISTRY, v.19, n.4, p.1477-1481, 2011

0968-0896

http://producao.usp.br/handle/BDPI/30079

10.1016/j.bmc.2010.12.056

http://dx.doi.org/10.1016/j.bmc.2010.12.056

Idioma(s)

eng

Publicador

PERGAMON-ELSEVIER SCIENCE LTD

Relação

Bioorganic & Medicinal Chemistry

Direitos

restrictedAccess

Copyright PERGAMON-ELSEVIER SCIENCE LTD

Palavras-Chave #Cathepsin V #Enzyme inhibitors #Natural products #Acridone alkaloids #LYSOSOMAL CYSTEINE PROTEASES #GLUTINOSA BL. MERR #CANCER-CELL LINES #SWINGLEA-GLUTINOSA #DRUG TARGETS #DESIGN #PROTEINASE #Biochemistry & Molecular Biology #Chemistry, Medicinal #Chemistry, Organic
Tipo

article

original article

publishedVersion