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

Abstract

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.

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

“…102 Use of a fluorescently labeled lacticin 481 analogue showed localization in rod-shaped bacteria that is consistent with the reported localization of lipid II. 140 The MOA of nukacin ISK-1 (15) has been investigated by using the two-component antibiotic-sensing system LiaRS from B. subtilis. LiaRS is activated by cell wall-active antibiotics that 12), lacticin 481 (13), bovicin HJ50 ( 14), nukacin ISK-1 (15), plantaricin C ( 16), and an alternative representation of plantaricin C (17).…”

“…The colocalization of genes encoding the biosynthetic proteins with those encoding the substrate peptide facilitates prediction of the entire biosynthetic pathway. Growing interest in the potential of RiPP therapeutics has been spurred by the discovery of compounds with antibacterial, antifungal, antinociceptive, , antiviral, and antitumor − activities. The myriad activities of RiPPs serve to emphasize how post-translational modifications have allowed molecular evolution of structures that exploit a wide range of biological targets in different domains of life.…”

Semisynthetic Macrocyclic Lipo-lanthipeptides Display Antimicrobial Activity Against Bacterial Pathogens

“…RiPPs have been shown to cover a variety of different bioactivities, i . e ., antibacterial, antitumor, and antiviral, 4 , 46 − 48 and an increasing number of engineered new-to-nature RiPP therapeutics is being reported. 4 , 6 , 21 , 25 , 48 The approach described here, where non-RiPP peptides are produced as RiPPs, combined with the identification of the CinM leader recognition site described earlier in this study, could be an interesting approach to the developments of new antimicrobials by engineering hybrid peptides.…”

Improved Database Filtering Technology Enables More Efficient Ab Initio Design of Potent Peptides against Ebola Viruses

“…Likewise, human cathelicidin LL-37, another key AMP, also demonstrated antiviral activity against SARS-CoV-2 [ 16 ]. These antiviral peptides can work through different mechanisms, ranging from immune regulation to direct inactivation via membrane disruption [ 17 , 18 , 19 , 20 ]. Hence, natural AMPs may be engineered into new therapeutics to help control these viruses [ 11 , 12 , 21 , 22 , 23 ].…”