Design, synthesis and inhibition activity of novel cyclic peptides against protein tyrosine phosphatase A from Mycobacterium tuberculosis.
Mycobacterium tuberculosis, the causative agent for tuberculosis has employed several signalling molecules to sense the host cellular environment and act accordingly. For example, protein tyrosine phosphatase A (MPtpA) of M. tuberculosis, a signalling protein belonging to the tyrosine phosphatase superfamily, is involved in phagocytosis and is active in virulent mycobacterial form. Starting from a β-lactam framework a new class of structure based cyclic peptide (CP) inhibitors was designed. The synthesis involves a crucial intramolecular transamidation via a ring opening reaction. All the compounds show moderate to good inhibitory activities against MPtpA in micromolar concentrations. The results of inhibition kinetics suggest mixed mode of inhibition. The binding constant determined from circular dichroism (CD) and fluorescence quenching studies shows strong binding of the hydrophilic side chain of CPs with the enzyme active site residues. All these are well supported by docking studies.
Department of Chemistry, Department of Biotechnology, Indian Institute of Technology, Kharagpur, India.
Koushik
K
Chandra
Debajyoti
D
Dutta
Amit K
AK
Das
Amit
A
Basak
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002942:Circular Dichroism; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013050:Spectrometry, Fluorescence
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C414465:MptpA protein, Mycobacterium tuberculosis; D010456:Peptides, Cyclic; D017027:Protein Tyrosine Phosphatases