Jayanta Chatterjee

Jayanta Chatterjee

Assistant Professor
Indian Institute of Science
Bangalore
India
 (91) 802-293-2053
 jayanta@iisc.ac.in

Abstract

Can Amide Bond Thionation Improve the Pharmacological Landscape of Therapeutic Peptides?

Solvation of an amide bond is a crucial factor that impedes the membrane permeability of peptides. 1, 2 Therefore, desolvation of the amide groups either by direct chemical modification or via conformational control allows for improving their passive membrane permeability. The membrane permeability of cyclosporine A has been the source of inspiration to utilize N-methylation for improving the membrane permeability of cyclic peptides and has led to the identification of several orally bioavailable peptides and scaffolds. 3 However, curiously, the carbonyl oxygen (C=O) has never been utilized to assess its significance in amide bond desolvation.

Scientific Figure

Thus, we critically analyzed the desolvation of amide bonds by sequentially occluding both the hydrogen bond donor and acceptor property by N-methylation and thioamidation, 4 respectively. Desolvation of an amide bond enhanced the lipophilicity of model dipeptides, where surprisingly, thioamidation showed a stronger effect than N-methylation. Consequently, monothioamidated model macrocyclic peptides were synthesized that showed increased lipophilicity than the parent peptide. Remarkably, several monothioamidated analogs showed significantly improved membrane permeability than the all-oxo cyclic peptide. Conformational analyses indicated that a thioamide substitution increases the lipophilicity of the macrocyclic peptide due to a combination of thiopeptide-bond desolvation and amide HN shielding due to conformational restriction. 5 The structural rigidity subsequently leads to the protection of the thioamidated macrocyclic peptides against proteolytic digestion in gastrointestinal fluids and blood plasma. We observed a good correlation between structural rigidity, transcellular-permeability, gastrointestinal stability and in vitro intrinsic clearance against liver microsomes of the monothioamidated macrocyclic peptides.

Therefore, a systematic single atom substitution (O to S) in the amide backbone of macrocyclic peptides show remarkable potential to increase their half-life in biological fluids and enhance their membrane permeability that will have direct impact on the oral bioavailability of macrocyclic peptides.

Authors

Jayanta Chatterjee

Affiliations

Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India

Citations

1. P.S. Burton, R. A. Conradi, A. R. Hilgers, N. F. H. Ho, L. L. Maggiora, J. Control. Release, 1992, 19, 87-98.
2. T. Rezai, B. Yu, G. L. Millhauser, M. P. Jacobson, R. S. Lokey, J. Am. Chem. Soc., 2006, 128, 2510-2511.
3. A. F. B. Räder, M. Weinmüller, F. Reichart, A. Schumacher-Klinger, S. Merzbach, C. Gilon, A. Hoffman, H. Kessler, Angew. Chem. Int. Ed., 2018, 57, 14414-14438.
4. S. Mukherjee, H. Verma, J. Chatterjee, Org. Lett., 2015, 17, 3150-3153.
5. H. Verma, B. Khatri, S. Chakraborti, J. Chatterjee, Chem. Sci., 2018, 9, 2443-2451.

Lecture Images

Jayanta Chatterjee presenting at APS2019 Jayanta Chatterjee presenting at APS2019 Jayanta Chatterjee presenting at APS2019