Green Chemistry in Peptide Therapeutics: Leading the Way from the Beginning
In recent years, the field of peptide therapeutics has seen a surge of interest in cyclic peptides, driven by their unique properties and potential as active pharmaceutical ingredients (APIs). Cyclic peptides are particularly appealing due to their ability to be designed with desirable membrane solubility and oral absorption properties, which opens up the opportunity to target intracellular receptors and proteins effectively.
One of the key advantages of cyclic peptides is their rigid structure, which presents a large surface area capable of interacting with protein-protein interfaces. This makes them ideal candidates for disrupting protein interactions that are otherwise challenging to target with small molecules.
The development and screening of complex cyclic peptide libraries, especially those incorporating non-canonical amino acids, have become standard practices in many research laboratories. This advancement is exemplified by companies like Peptidream and RA Pharma, which have demonstrated success using mRNA libraries. The incorporation of non-canonical amino acids significantly expands the diversity and properties of these peptides, overcoming the limitations of the 20 natural amino acids.
However, once a promising lead is identified, scaling up the production of these peptides presents significant challenges. The synthesis of large quantities of non-canonical amino acids required for clinical programs is often complex and expensive, potentially delaying projects and increasing costs. To address this, several major pharmaceutical companies are investing in innovative platforms for the production of non-canonical building blocks that are both scalable and cost-effective.
An excellent example of such innovation is highlighted in an open-access article by Merck & Co. Inc. The article outlines a general approach for producing beta-branched aryl chiral amino acids using biocatalysis. Merck’s approach focuses on three key prerequisites: i) conducting reactions in water, ii) using an enzyme with broad selectivity and high chiral specificity, and iii) utilizing a cheap and readily available substrate as the amino donor.
In their study, Merck successfully used lysine as an amino donor, racemic aryl keto acids as the beta-branched starting materials, and transaminase as the enzyme to achieve high-yield, stereoselective reactions. Remarkably, the reactions proceeded with yields averaging above 70%, consistently producing the S,S configuration.
These beta-branched amino acids are now likely being incorporated into cyclic peptide libraries produced by Merck and its partners. This development is particularly exciting because the ability to lock the conformation of sidechain rotamers is a critical parameter for the success of these libraries.
In our April Journal Club edition, we discussed the necessity for peptide chemistry to become lean and green, emphasizing the adoption of green chemistry early in the API lifecycle. Merck’s efforts exemplify this principle by integrating green chemistry into their lead compound library screening process (we hope), ensuring that the compounds selected can be produced sustainably.
This article from Merck provides a compelling case study of how green chemistry can be implemented effectively in peptide therapeutics, paving the way for more sustainable and efficient drug development processes.
Article Citation: Dunham N, Ray R, Eberle C, Winston M, Newman J, Gao Q, et al. Efficient Access to β-Branched Noncanonical Amino Acids via Transaminase-Catalyzed Dynamic Kinetic Resolutions Driven by a Lysine Amine Donor. ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-qm6pl. This content is a preprint and has not been peer-reviewed. The authors have deposited a ChemRxiv open-access version at https://chemrxiv.org/engage/chemrxiv/article-details/660da6f221291e5d1dfe8287.
Matteo Villain, PharmD.
Member, BPF Scientific Advisory Board
linkedin.com/in/matteo-villain
Read previous editions of the BPF Journal Club series: https://www.boulderpeptide.org/journal-club