Beyond function: Engineering improved peptides for therapeutic applications

Abstract

Peptides are a promising source of new therapeutics, but the biophysical characteristics of natural peptides, including their stability and propensity to aggregate, can limit their success. Protein engineering offers powerful tools to improve the properties of peptides for biological applications. In this review, we explain rational design, directed evolution, and computational methods and how these methods can be applied to improving the characteristics of peptides. We also provide a discussion of engineering the thermodynamic stability, self‐assembly, reduced aggregation, proteolytic stability, and binding affinity and specificity of peptides, along with a perspective on future directions in engineering therapeutic peptides.

Lessons from a Single Amino Acid Substitution: Anticancer and Antibacterial Properties of Two Phospholipase A2-Derived Peptides

“…The years of evolution of these compounds reveal clues for the selection of new hits, and simultaneously, new data to refine the statistical and computational models of prediction [29,30]. The bioengineering and optimization of antibacterial and antitumor peptides have been automated today [31,32]. The development of tools, methods, and computational algorithms has allowed significant advances in the peptide design and the understanding of critical interactions for the mechanism of action of these molecules [33,34].…”

Combating Antimicrobial Resistance With New-To-Nature Lanthipeptides Created by Genetic Code Expansion

“…Numerous conventional protein engineering approaches such as site-directed mutagenesis, directed evolution and various computational tools aid synthetic biologists and biochemists to selectively diversify the properties of expressed therapeutic peptides. These include manipulations of thermodynamic stability, increased bioavailability, reduced aggregation or enhanced specificity and proteolytic stability ( Adhikari et al, 2019 ). In addition, the implementation of in vitro and in vivo approaches in combination with genome mining data and high-throughput screening strategies has opened up unprecedented opportunities to modify and even improve antimicrobial activity, manipulate the physicochemical properties and widening of the antibacterial spectrum in the production of lantibiotics ( Field et al, 2015 ).…”

Modular Approach to Enhance the Bioactivity of Peptides

“…The source of BPs can be from natural peptides of endogenic origin, or it can be synthesized in the lab based on rational design or screening. Herein we demonstrate how a BP of interest can be modified to a highly effective research tool as well as therapeutic lead with minimal modifications that can be done in many labs or ordered for a reasonable price [1,2]. Phosphatase and tensin homolog induced kinase 1 (Pink1) is serine/threonine kinase.…”