Design of Artificial Enzymes: Insights into Protein Scaffolds

The design of artificial enzymes has emerged as a promising tool for the generation of potent biocatalysts able to promote new-to-nature reactions with improved catalytic performances, providing a powerful platform for wide-ranging applications and a better understanding of protein functions and structures. The selection of an appropriate protein scaffold plays a key role in the design process. This review aims to give a general overview of the most common protein scaffolds that can be exploited for the generation of artificial enzymes. Several examples are discussed and categorized according to the strategy used for the design of the artificial biocatalyst, namely the functionalization of natural enzymes, the creation of a new catalytic site in a protein scaffold bearing a wide hydrophobic pocket and de novo protein design. The review is concluded by a comparison of these different methods and by our perspective on the topic

Expanding the Genetic Code:Incorporation of Functional Secondary Amines via Stop Codon Suppression

Enzymes are attractive catalysts for chemical industries, and their use has become a mature alternative to conventional chemical methods. However, biocatalytic approaches are often restricted to metabolic and less complex reactivities, given the limited amount of functional groups present. This drawback can be addressed by incorporating non-canonical amino acids (ncAAs) harboring new-to-nature chemical groups. Inspired by organocatalysis, we report the design, synthesis and characterization of a panel of ncAAs harboring functional secondary amines and their cellular incorporation into different protein scaffolds. D/L-pyrrolidine- and D/L-piperidine-based ncAAs were successfully site-specifically incorporated into proteins via stop codon suppression methodology. To demonstrate the utility of these ncAAs, the catalytic performance of the obtained artificial enzymes was investigated in a model Michael addition reaction. The incorporation of pyrrolidine- and piperidine- based ncAAs significantly expands the available toolbox for protein engineering and chemical biology applications.</p

The Total Synthesis of Chondrochloren A.

The first total synthesis of chondrochloren A is accomplished using a 1,2-metallate rearrangement addition as an alternative for the Nozaki-Hiyama-Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z-enamide is accomplished using a Z-selective cross coupling of the corresponding amide to a Z-vinyl bromide

Selective synthesis of methyl dithienyl-glycolates

An efficient selective synthesis of methyl dithienyl-glycolates has been developed. The interest of this two steps protocol resides in the possibility of synthesized either methyl 2,2-dithienyl glycolate \u2013 the target intermediate for the preparation of anticholinergic agents \u2013 or its regio-isomer methyl 2,3-dithienyl glycolate \u2013 the most critical precursor of anticholinergic drug impurity

The 1,2,3-triazole ring as a bioisostere in medicinal chemistry

1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compounds characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active molecules. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples

Synthesis of Thicolchicine-Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders

Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with \u3b1-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the \u3b1-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules