Novel isomannide-based peptide mimetics containing a tartaric acid backbone as serine protease inhibitors.

Autor: Abrahim-Vieira, Bárbara, Costa, Emmerson, A. Azevedo, Pedro, Portela, Aline, Dias, Luiza, Pinheiro, Sergio, Tanuri, Amilcar, Capaccia, Anne, Ventura, Gustavo, Mohana-Borges, Ronaldo, Rodrigues, Carlos, Souza, Alessandra, Muri, Estela
Zdroj: Medicinal Chemistry Research; Dec2014, Vol. 23 Issue 12, p5305-5320, 16p
Abstrakt: Hepatitis C viral infection is a cause of chronic liver disease, and current therapies are only effective in 50 % of patients. Serine proteases, which are present in both hepatitis C virus (HCV) and the dengue virus, are the most studied class of proteolytic enzymes and are the primary targets for drug development in this field. In this paper, we describe the synthesis of a novel class of isomannide-based peptide mimetic compounds based on a tartaric acid backbone. Our data showed that substitutions at position 168 (D168A) and 170 (V170A) conferred low-level resistance against compound 5a3, whereas substitutions at position 155 (R155K) and 156 (A156V) conferred no resistance. These data suggest that even though compound 5a3 is a noncompetitive inhibitor; it is able to interact with important residues located near the catalytic site. In addition, this novel compound class exhibits potent antiviral activity against variants carrying resistance mutations to boceprevir and telaprevir. Our docking studies showed important interactions, including hydrogen bonds and a π-π interaction, between compound 5a3 and residues of the allosteric site of NS3/4A. Biological and theoretical results indicate that 5a3 is a promising lead compound for the development of new drugs targeting HCV infection. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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