Site-selective modification of peptide backbones

The site-selective modification of peptide backbones allows an outstanding fine-tuning of peptide conformation, folding ability, and physico-chemical and biological properties. However, to achieve selectivity in the core of these biopolymers is challenging. In the last few years, many advances towards this goal have been developed. This review addresses the selective modification of Cα- and N-positions, from the use of “customizable units” to the residue-directed introduction of substituents. The site-selective modification of the peptide bond, i.e. the formation of thioamides or heterocycles, which alters backbone rigidity and ability to form hydrogen bonds or recognition by enzymes, is also described. Moreover, not only the modifications in internal backbone positions, but also in the N- and C-termini are discussed. In addition to chemical methodologies, the review addresses some reactions, catalyzed by natural or engineered enzymes, that afford unprecedent regio- and stereoselectivity in backbone modifications.
This work was mainly financed by project ProID2020010134 (Subvenciones a la Realización I + D Mª Carmen Betancourt y Molina, ACIISI-Gobierno de Canarias, with European Funds for Regional Development-FEDER) with contributions from project APOGEO (MAC/1.1.b./226, Cooperation Program INTERREG-MAC 2014–20 with FEDER funds, as well as Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015-01-807. D. H. also acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife, Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). C. J. S. is currently recipient of a “Agustín de Betancourt”-Tenerife 2030 postdoctoral grant (Universidad de La Laguna-Cabildo de Tenerife, cofinanced by MEDI & FDCAN Funds). I. R-E. thanks CONACYT for Catedra contract 942.