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Mechanisms of action of ribosomally synthesized and posttranslationally modified peptides (RiPPs).

ABSTRACT: Natural products remain a critical source of medicines and drug leads. One of the most rapidly growing superclasses of natural products is RiPPs: ribosomally synthesized and posttranslationally modified peptides. RiPPs have rich and diverse bioactivities. This review highlights examples of the molecular mechanisms of action that underly those bioactivities. Particular emphasis is placed on RiPP/target interactions for which there is structural information. This detailed mechanism of action work is critical toward the development of RiPPs as therapeutics and can also be used to prioritize hits in RiPP genome mining studies.

SUBMITTER: Cao L

PROVIDER: S-EPMC8183687 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Antiviral activities and applications of ribosomally synthesized and post-translationally modified peptides (RiPPs).

Project description:The emergence and re-emergence of viral epidemics and the risks of antiviral drug resistance are a serious threat to global public health. New options to supplement or replace currently used drugs for antiviral therapy are urgently needed. The research in the field of ribosomally synthesized and post-translationally modified peptides (RiPPs) has been booming in the last few decades, in particular in view of their strong antimicrobial activities and high stability. The RiPPs with antiviral activity, especially those against enveloped viruses, are now also gaining more interest. RiPPs have a number of advantages over small molecule drugs in terms of specificity and affinity for targets, and over protein-based drugs in terms of cellular penetrability, stability and size. Moreover, the great engineering potential of RiPPs provides an efficient way to optimize them as potent antiviral drugs candidates. These intrinsic advantages underscore the good therapeutic prospects of RiPPs in viral treatment. With the aim to highlight the underrated antiviral potential of RiPPs and explore their development as antiviral drugs, we review the current literature describing the antiviral activities and mechanisms of action of RiPPs, discussing the ongoing efforts to improve their antiviral potential and demonstrate their suitability as antiviral therapeutics. We propose that antiviral RiPPs may overcome the limits of peptide-based antiviral therapy, providing an innovative option for the treatment of viral disease.

| S-EPMC7853169 | biostudies-literature

Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria.

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Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs).

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Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides.

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| S-EPMC9826248 | biostudies-literature

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Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides.

Project description:Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a large class of natural products that are remarkably chemically diverse given an intrinsic requirement to be assembled from proteinogenic amino acids. The vast chemical space occupied by RiPPs means that they possess a wide variety of biological activities, and the class includes antibiotics, co-factors, signalling molecules, anticancer and anti-HIV compounds, and toxins. A considerable amount of RiPP chemical diversity is generated from cyclisation reactions, and the current mechanistic understanding of these reactions will be discussed here. These cyclisations involve a diverse array of chemical reactions, including 1,4-nucleophilic additions, [4 + 2] cycloadditions, ATP-dependent heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted.

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Project description:To face the current antibiotic resistance crisis, novel strategies are urgently required. Indeed, in the last 30 years, despite considerable efforts involving notably high-throughput screening and combinatorial libraries, only few antibiotics have been launched to the market. Natural products have markedly contributed to the discovery of novel antibiotics, chemistry and drug leads, with more than half anti-infective and anticancer drugs approved by the FDA being of natural origin or inspired by natural products. Among them, thanks to their modular structure and simple biosynthetic logic, ribosomally synthesized and posttranslationally modified peptides (RiPPs) are promising scaffolds. In addition, recent studies have highlighted the pivotal role of RiPPs in the human microbiota which remains an untapped source of natural products. In this review, we report on recent developments in radical SAM enzymology and how these unique biocatalysts have been shown to install complex and sometimes unprecedented posttranslational modifications in RiPPs with a special focus on microbiome derived enzymes.

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