RshA mimetic peptides inhibiting the transcription driven by a Mycobacterium tuberculosis sigma factor SigH

Abstract

SigH, an alternative sigma factor in Mycobacterium tuberculosis, is a central regulator in responses to the oxidative and heat stress. This SigH activity is specifically controlled by an anti-sigma factor RshA during expression of stress-related genes. Thus, the specific interaction (k(on) = 1.15 x 10(5) (M-1 s(-1)), k(off) = 1.7 x 10(-3) (s(-1)), K-D = 15 nM, determined in this study) between SigH and RshA is crucial for the survival and pathogenesis of M. tuberculosis. Using phage-display peptide library, we defined three specific regions on RshA responsible for SigH binding. Three RshA mimetic peptides (DAHADHD, AEVWTLL, and CTPETRE) specifically inhibited the transcription initiated by SigH in vitro. One of them (DAHADHD) diminished the extent of binding of RshA to SigH in a dose-dependent manner. The binding affinity (KD) of this peptide to Si.-H was about 1.2 mu M. These findings might provide some insights into the development of new peptide-based drugs for TB. (c) 2005 Elsevier Inc. All rights reserved.