Aminovinyl Cysteine Containing Peptides: A Unique Motif That Imparts Key Biological Activity

Abstract

Natural products that contain distinctive chemical functionality can serve as useful starting points to develop Nature’s compounds into viable therapeutics. Peptide natural products, an under-represented class of medicines, such as ribosomally synthesized and post-translationally modified peptides (RiPPs), often contain noncanonical amino acids and structural motifs that give rise to potent biological activity. However, these motifs can be difficult to obtain synthetically, thereby limiting the transition of RiPPs to the clinic. Aminovinyl cysteine containing peptides, which display potent antimicrobial or anticancer activity, possess an intricate C-terminal ring that is critical for bioactivity. To date, successful methods for the total chemical synthesis of such peptides are yet to be realized, although several advancements have been achieved. In this perspective, we review this burgeoning class of aminovinyl cysteine peptides and critically evaluate the chemical strategies to install the distinct aminovinyl cysteine motif.

Peptide and Protein Cysteine Modification by Virtue of Highly Chemo-, Regio- and Stereoselective Hydrosulfuration of Ynamide

“…The simple and mild reaction conditions, excellent chemo-, regio-and stereoselectivities of basepromoted ynamide β-addition encouraged us to expand such chemistry to hydrosulfuration by employing thiols as the nucleophile. If successful, we might provide an e cient approach to construct S-[(Z)-2aminovinyl]-D-cysteine (AviCys) subunit which is a unique motif widely found in lanthipeptide natural products and plays a crucial role in their potent antimicrobial or anticancer activity [35] . Obviously, this method would also provide a novel and promising Cys modi cation strategy, which might address the notorious issues of current strategies.…”

Substrate plasticity of dehydratase SpaKC from the biosynthesis of thiosparsoamide

“…In addition to the class‐defining thioamide motifs, thioamitides often contain a 2‐aminovinyl‐cysteine (AviCys) crosslinked macrocycle at the C‐terminus (Figure 1). AviCys motifs are also found in a variety of RiPPs, including lanthipeptides (e.g., epidermin), lipolanthines (e.g., microvionin), and linaridins (e.g., cypemycin), implying that this cyclic scaffold is of biological importance 4–19 . The origin of AviCys motifs in thioamitides is recently revealed by Liu group during the investigation of the biosynthesis of TVA produced by the tva S‐87 gene cluster in Streptomyces sp.…”

“…1,3 Thioamitides are a subgroup of RiPPs that possess potent antimicrobial, antiproliferative, and pro-apoptotic activities. [4][5][6] In addition to the class-defining thioamide motifs, thioamitides often contain a 2-aminovinyl-cysteine (AviCys) crosslinked macrocycle at the C-terminus (Figure 1). AviCys motifs are also found in a variety of RiPPs, including lanthipeptides (e.g., epidermin), lipolanthines (e.g., microvionin), and linaridins (e.g., cypemycin), implying that this cyclic scaffold is of biological importance.…”

“…AviCys motifs are also found in a variety of RiPPs, including lanthipeptides (e.g., epidermin), lipolanthines (e.g., microvionin), and linaridins (e.g., cypemycin), implying that this cyclic scaffold is of biological importance. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] The origin of AviCys motifs in thioamitides is recently revealed by Liu group during the investigation of the biosynthesis of TVA produced by the tva S-87 gene cluster in Streptomyces sp. NRRL S-87, showing that this path relies on four dedicated proteins: phosphotransferase TvaC S-87 , lyase TvaD S-87 , kinase homolog TvaE S-87 , and flavoprotein TvaF S-87 .…”

“…Upon completion of enzymatic modifications, the leader and/or follower peptides are removed to produce the final product 1,3 . Thioamitides are a subgroup of RiPPs that possess potent antimicrobial, antiproliferative, and pro‐apoptotic activities 4–6 . In addition to the class‐defining thioamide motifs, thioamitides often contain a 2‐aminovinyl‐cysteine (AviCys) crosslinked macrocycle at the C‐terminus (Figure 1).…”