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

Yuxin Fu,Ate H. Jaarsma,Oscar P. Kuipers

doi:10.1007/s00018-021-03759-0

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.

Highlights

IntroductionViruses represent a major cause of disease and mortality worldwide. great progress has been made in virus control, approved antiviral therapies for the majority of viruses are still lacking [1–4]
We explore the antiviral ribosomally synthesized and post-translationally modified peptides (RiPPs) that exist in nature, their mechanism of action (Fig. 1), the possibilities for the engineering of them, and discuss their potential for therapeutic application
RiPPs commonly have cyclic structures conferred by post-translational modifications, which impart them with remarkable proteolytic stability, binding specificity, membrane permeability and even better oral availability

Summary

Introduction

Viruses represent a major cause of disease and mortality worldwide. great progress has been made in virus control, approved antiviral therapies for the majority of viruses are still lacking [1–4]. Since the only antiviral members of the Möbius subfamily, kalata B1 [74], Varv peptide E [75], cycloviolacin O14 and O24 [68] were reported to have a comparable HIV-inhibitory activity to bracelet cyclotides, but with a reduced toxicity to the target cells, they can be regarded as more promising leads in anti-HIV therapy than their bracelet counterparts. Loops 5 and 6 play an important role in the antiviral binding and hemolytic activity of kalata B1, genetic algorithms were used to select peptides based on HIV-1 gp120-CD4 hotspot regions for grafting in between these two loops which was followed by molecular modeling techniques to assess the chimeric kalata B1 (Fig. 3b), screening out two modified kalata B1s that exhibited better interaction energies (36.6% and 22.8%, respectively) when binding to HIV-1 gp120 compared to wild-type kalata B1, in spite of no in vitro validation These results open the way for engineering cyclotides-based antivirals with different binding activity and enhanced inhibitory activity. Other technologies and materials are being developed for new antiviral formulas, such as tenofovir in a gel formulation, which appears safe and effective in preventing HIV infection, and has great potential as a antiretroviral microbicide [122]

Screening methods to identify novel antiviral RiPPs

Findings

Conclusions