Study of the cis-trans Isomerization of the Amino-Acyl prolyl Peptide Bond. Application to the Design of Novel Inhibitors of Immunophilins

Christophe      Dugave

doi:10.2174/1385272023373301

Abstract

Cis-trans isomerization of amide bonds plays a crucial role in protein structure as well as in the activity of peptides. In particular, the amino acyl-proline cis-trans interconversion is one of the limiting steps of protein folding and is accelerated by a family of proteins called immunophilins or peptidyl-prolyl isomerases (PPIases). Consequently, PPIases are implicated in many biological processes such as protein expression, mitosis and cellular communication. They also play a role in immunosuppression as well as in several pathologies such as AIDS and severe neurodegenerative disorders. Therefore, immunophilins are attractive targets for the design of novel therapeutics. In this review, the design of selective PPIases inhibitors will be detailed on the basis of structural data and structure-activity realtionship studies. The preparation and biochemical evaluation of new molecules derived from immunosuppressive inhibitors of immunophilins such as cyclosporin and FK506 will be tackled. Results, collated with structural data, will then be used with view to developing potent and selective inhibitors devoid of immunosuppressive activity. In particular the design and synthesis of ground-state inhibitors and non-isomerisable analogs of the amino acyl-proline moiety, including constrained proline, proline mimetics and endogenous cyclophilin ligands, will be explained. Finally, we will focus on the synthesis of transition-state analog inhibitors of the PPIases including ketoamides, phosphonamides and sulfonamides.

Keywords: cis-trans Isomerization, Amino-Acyl prolyl, Peptide Bond, Immunophilins, homoserine, hexamethyldisilazane, imidazolyl, N-methyl-valine, rapamycin, trimethylsilyl