Catalytic sieving of ATC gamma-peptide foldamers – CatFold

Catalytic processes form the fundamentals of modern chemical and pharmaceutical industries. In the developed industrial countries catalytic processes create about 20% of the Gross Domestic Product (GDP) making production of catalysts a strategic importance for the country economy. Chemical catalysts are used primarily in industrial processes of fine chemicals, so that toxicological drawbacks with compounds that often contain heavy metals arise mostly in production and recycling. At the opposite of small molecule catalysts, biocatalysts offer an attractive alternative to conventional chemical methods. Enzymes are powerful catalysts typically non-toxic and environmentally friendly capable of performing remarkably difficult chemical transformations with relative ease, unmatched substrate and product selectivity. However due to unsatisfactory stabilities and laborious isolation processes, they are only exceptionally used in large-scale production, even though a growing demand is expected because of their potential for enantiomer-pure synthesis.
Aspiring to imitate enzymatic efficiencies, chemists have attempted to create “synthetic enzymes”. Over the past several decades peptides and peptide-based molecules have emerged as promising minimal enzymatic systems but the difficulty to control their three-dimensional limits their use to re-create all of the desirable characteristics for an enzyme-like catalyst. Over the last years, new synthetic systems named “foldamers”, mimicking the protein secondary structures (helices, sheets and ribbons) were developed. They are defined as artificial oligomers with high conformational stability and structural predictabilities. Substantial results were obtained that have been patented for material and biomedical applications. Recently, few companies as Longevity Biotech Inc were created, highlighting the high scientific and economic impact of the foldamer technology. Nevertheless, despite this success in particular as recognition elements to inhibit protein-protein interactions, their potential for modular catalyst design has been little studied. In this context, the CatFold project is devoted to the development of bio-inspired foldamer catalysts and one major question to be addressed is to what extent a small foldamer can be adapted to achieve catalytic functions.
Objectives: Following the guidelines of the call D-3 - Axis 4, the proposed program concerns 1/ the design and the structural characterization of molecular edifices with predictable folding properties and 2/ the systematic study of structure-function relationships in the area of enantioselective organo-catalysis. In this context, the CatFold project aims to use a newly heteroaromatic gamma–peptide foldamer scaffold to template modular catalysts: we intend to combine the diverse synthetic toolbox provided by small-molecule catalysis with precise molecular recognition elements bring by foldamers. One central feature will be to systematically explore the connection between foldamer sizes and/or shapes, and both reactivity and (enantio-) selectivity. To the best of our knowledge, the opportunity of using peptide-based foldamer as tunable catalytic framework has been little explored. If successful, the project purposes will deliver innovative tools for designing synthetic enzyme-like catalysts starting from molecular constructions with controlled three-dimensional shape. The CatFold project is particularly groundbreaking from a technological aspect and is therefore likely to impulse significant renewal in organo-catalyst development.