Journal Article

Unleashing the Antiviral Potential of Stapled Peptides: A New Frontier in Combating Human Neurotropic Viral Infections

Rahangdale, Rakesh, Santhoshkumar, Puttur, Patil, Sanskruti, Pasupuleti, Mukesh, Hariharapura, Raghu Chandrashekar

2025

Overview

Neurotropic viral infections continue to pose significant global health challenges, with pathogens such as herpes simplex virus (HSV), varicella‐zoster virus, human immunodeficiency virus, poliovirus, enteroviruses, parechovirus, West Nile virus and Japanese encephalitis virus driving the search for more effective therapeutic interventions. Current antiviral strategies, including small molecules and monoclonal antibodies, often face limitations such as drug resistance, narrow spectrum activity and adverse side effects, underscoring the need for alternative approaches. Antiviral peptides are emerging as potential therapeutic agents against these viral infections as entry and fusion inhibitors. However, their clinical development is limited by poor stability, low bioavailability and insufficient cellular penetration. To address these limitations, peptide stapling, a chemical modification that stabilises peptide α‐helices through covalent linkage, has emerged as a transformative technique to enhance the therapeutic potential of peptides, especially in antiviral drug development. Stapling techniques, including hydrocarbon staples, lactam bridges and metal‐coordination bonds, are explored for their ability to improve peptide stability, bioavailability and target binding affinity. This review examines the application of stapling in the development of antiviral peptides with a focus on stapled peptides targeting viral fusion and entry mechanisms, highlighting their potential against neurotropic viruses such as HSV and influenza. By integrating the structural rigidity conferred by stapling, these constructs promise to overcome delivery barriers and achieve superior antiviral efficacy. This paper underscores the pivotal role of peptide stapling by highlighting recent advancements in antiviral therapeutics and presents a roadmap for future research into multifunctional stapled peptides. Human neurotropic viruses like SARS‐CoV‐2, HSV, HOPV and RSV pose significant risks due to their ability to invade and persist in the nervous system. Stapled peptides represent a promising therapeutic approach with enhanced stability, target affinity and bioavailability, emerging as an effective strategy for neutralising human neurotropic viruses.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Amides / Antimicrobial agents / Antiviral Agents - chemistry / Antiviral Agents - pharmacology / Antiviral drugs / antiviral peptides / Bacterial infections / Bioavailability / Biological products / Cancer / Chemical modification / COVID-19 / Drug development / Drug resistance / Ebola virus / Effectiveness / Encephalitis / Enteroviruses / Epidemiology / Genomes / Global health / Helices / Herpes simplex / HIV / Human immunodeficiency virus / Humans / Influenza / Measles / Medical research / Monoclonal antibodies / Nervous system / peptide stability / peptide stapling / Peptides / Peptides - chemistry / Peptides - pharmacology / Peptides - therapeutic use / Pharmacology / Proteins / Public health / Review / Rigidity / RNA polymerase / Severe acute respiratory syndrome coronavirus 2 / Side effects / Stability / Staples / Therapeutic applications / therapeutic peptides / Toxicity / Varicella / Vector-borne diseases / Viral infections / viral inhibition / Virus Internalization - drug effects / West Nile virus / Zika virus / α‐Helices