Design, Synthesis, and Experimental Validation of Peptide Ligands Targeting Mycobacterium tuberculosis sigma Factors

Vishwanath, Sneha and Banerjee, Sunaina and Jamithireddy, Anil K and Srinivasan, Narayanaswamy and Gopal, Balasubramanian and Chatterjee, Jayanta (2017) Design, Synthesis, and Experimental Validation of Peptide Ligands Targeting Mycobacterium tuberculosis sigma Factors. In: BIOCHEMISTRY, 56 (16). pp. 2209-2218.

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Abstract

Transcription in prokaryotes is a multistep process and is :primarily regulated at the initiation stage. sigma factors are involved in promoter recognition and thus govern prokaryotic gene expression. Mycobacterium tuberculosis (MO) sigma factors have been previously suggested as important drug targets through large-scale genome analyses. Here we demonstrate the feasibility of specific targeting of Mtb sigma factors using designed peptides. A peptide library was generated using three-dimensional structural features corresponding to the interface regions of sigma factors and the RNA polymerase. In silico optimization of the peptides, employing structural as well as sequence features, aided specific targeting of sigma(A) and sigma(B). We synthesized and characterized the best hit peptide from the peptide library along with other control peptides and studied the, interaction of these peptides with;sigma(B) using biolayer interferometry. The experimental data validate; the design strategy. These studies suggest the feasibility of designing specific peptides via in silico methods that bind sigma(B) with nanomolar affinity. We note that this strategy can be broadly applied to modulate prokaryotic transcription by designed peptides, thereby providing a tool for studying bacterial adaptation as well as host pathogen interactions in infectious bacteria.

Item Type:	Journal Article
Publication:	BIOCHEMISTRY
Additional Information:	Copy right for this article belongs to the AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	25 May 2017 09:30
Last Modified:	25 May 2017 09:30
URI:	http://eprints.iisc.ac.in/id/eprint/57050

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