Toward the Synthesis and Improved Biopotential of an N-methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria
Rajiv Dahiya,
Suresh Kumar,
Sukhbir Lal Khokra,
Sheeba Varghese Gupta,
Vijaykumar B. Sutariya,
Deepak Bhatia,
Ajay Sharma,
Shamjeet Singh,
Sandeep Maharaj
Affiliations
Rajiv Dahiya
Laboratory of Peptide Research and Development, School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, Saint Augustine, Trinidad and Tobago
Suresh Kumar
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, Haryana, India
Sukhbir Lal Khokra
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, Haryana, India
Sheeba Varghese Gupta
Department of Pharmaceutical Sciences, USF College of Pharmacy, University of South Florida, Tampa, FL 33612-4749, USA
Vijaykumar B. Sutariya
Department of Pharmaceutical Sciences, USF College of Pharmacy, University of South Florida, Tampa, FL 33612-4749, USA
Deepak Bhatia
Department of Pharmacogenomics, ICPH Fairfax Bernard J. Dunn School of Pharmacy, Shenandoah University, Fairfax, VA 22031, USA
Ajay Sharma
Department of Pharmacognosy, Amity Institute of Pharmacy, Amity University, Gwalior 474020, Madhya Pradesh, India
Shamjeet Singh
Laboratory of Peptide Research and Development, School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, Saint Augustine, Trinidad and Tobago
Sandeep Maharaj
Laboratory of Peptide Research and Development, School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, Saint Augustine, Trinidad and Tobago
An N-methylated analog of a marine bacteria-derived natural proline-rich tetracyclopeptide was synthesized by coupling the deprotected dipeptide fragments Boc-l-prolyl-l-N-methylleucine-OH and l-prolyl-l-N-methylphenylalanine-OMe. A coupling reaction was accomplished utilizing N,N′-Dicyclohexylcarbodidimde (DCC) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC·HCl) as coupling agents and Triethylamine (TEA) or N-methylmorpholine (NMM) as the base in the presence of the racemization suppressing agent. This was followed by the cyclization of the linear tetrapeptide fragment under alkaline conditions. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FTIR (Fourier-transform infrared spectroscopy), 1H NMR (Nuclear magnetic resonance spectroscopy), 13C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic potential against Megascoplex konkanensis, Pontoscotex corethruses, and Eudrilus eugeniae at a concentration of 2 mg/mL as well as improved antifungal activity against pathogenic dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 μg/mL, as compared to non-methylated tetracyclopeptide. Moreover, N-methylated tetracyclopeptide displayed significant activity against pathogenic Candida albicans.
