bioTCI: Biomolecular Targeted Covalent Inhibitor as a forefront drug platform

Targeted Covalent Inhibitors (TCIs), such as aspirin (Bufferin®), have a long history of more than 120 years, and most of them are synthetic small molecules. Instead, we have been developed larger “biomolecular” TCIs (bioTCIs) which can semi-permanently inhibit disease-related target proteins with little unwanted side-effects (Fig. A). Especially, as shown in Fig. B, we have achieved for the first time about:

1. Combinatorial screening ^(#1) of peptidic TCIs

2. Transforming DNA aptamers ^(#2) into TCIs

Including above, here we comprehensively review the past, current, and future bioTCI researches. As shown in the title and abstract, the review emphasizes the fundamental molecular mechanisms of a bioTCIs for potential antibody-drug substitute, and what is different between bioTCIs and conventional TCIs. We categorized bioTCIs into three different modalities (i.e., peptidic, nucleotidic, and proteinic ones), and their history of development over-viewed. Regardless of the modalities, all bioTCIs ameliorate the skepticism of small-molecule TCIs’ safety concerns because bioTCIs can stringently recognize and conjugate only to the target proteins. In addition, nucleotidic bioTCIs possess unique features, such as nuclease resistance and on-demand selective reversal with the CS antidote, which circumvents another major limitation to clinical translation of the nucleotidic aptamer drugs. To our knowledge, there is no published review article which examines nucleotidic TCIs.

Words explanation:

^#1 Combinatorial screening: a method for selecting TCIs from a large number (~10⁹) of candidate peptides

^#2 DNA aptamer: single-stranded DNA possessing target-binding ability

bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements

by Jay Yang, Yudai Tabuchi, Riku Katsuki, and Masumi Taki

Int. J. Mol. Sci. 2023, 24(4), 3525; https://www.mdpi.com/1422-0067/24/4/3525

In Topical Collection "State-of-the-Art Molecular Immunology in Japan"

We are seeking collaborators as well as Ph.D. students; UEC Tokyo has AiQuSci scholarship.