Affiliation:
1. Novartis Biomedical Research
Abstract
Abstract
As the demand for therapeutic peptides has increased over the last decades the toolbox for their synthesis is needing to expand as well. Biocatalytic methods to enhance and complement solid-phase peptide synthesis (SPPS) have been proposed, especially from natural product pathways that modify linear precursor peptides. In this paper, we investigated the synthetic capacity of three classes of enzymes (heterocyclase, macrocyclase, and oxidase) involved in cyanobactin production. With a combination of SPPS and natural as well as rationally engineered enzymes we have reconstituted this pathway in vitro to produce non-natural semi-synthetic cyclic peptides. Using a computationally guided library generation method we explored the current limitations of such a semi-synthetic approach. Finally, we showed that these enzymes can cooperate to produce a broad scope of peptide macrocycles that, to our knowledge, don’t occur naturally.
Publisher
Research Square Platform LLC
Reference31 articles.
1. Therapeutic peptides: current applications and future directions;Wang L;Signal Transduct Target Ther,2022
2. Thayer, A. M. Making Peptides At Large Scale. https://cen.acs.org/articles/89/i22/Making-Peptides-Large-Scale.html (2011).
3. Sustainable, cost-efficient manufacturing of therapeutic peptides using chemo-enzymatic peptide synthesis (CEPS);Pawlas J;Green Chemistry,2019
4. Estimated costs of production and potential prices for the WHO Essential Medicines List;Hill AM;BMJ Glob Health,2018
5. Approaches for enhancing oral bioavailability of peptides and proteins;Renukuntla J;Int J Pharm,2013