Patil Sanskruti, Rahangdale Rakesh, Pasupuleti Mukesh, Santhoshkumar Puttur, Hariharapura Raghu Chandrashekar
Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.
Microbiology Division, Council of Scientific and Industrial Research, Central Drug Research Institute, Lucknow, India.
Microb Biotechnol. 2025 Sep;18(9):e70221. doi: 10.1111/1751-7915.70221.
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.
嗜神经病毒感染继续给全球健康带来重大挑战，单纯疱疹病毒（HSV）、水痘带状疱疹病毒、人类免疫缺陷病毒、脊髓灰质炎病毒、肠道病毒、细小病毒、西尼罗河病毒和日本脑炎病毒等病原体推动了对更有效治疗干预措施的探索。包括小分子和单克隆抗体在内的当前抗病毒策略常常面临耐药性、窄谱活性和不良副作用等限制，这凸显了采用替代方法的必要性。抗病毒肽作为针对这些病毒感染的潜在治疗剂，正作为进入和融合抑制剂而崭露头角。然而，它们的临床开发受到稳定性差、生物利用度低和细胞穿透不足的限制。为了解决这些限制，肽环化修饰，一种通过共价连接稳定肽α螺旋的化学修饰，已成为一种变革性技术，可增强肽的治疗潜力，尤其是在抗病毒药物开发中。人们探索了包括烃类环化修饰、内酰胺桥和金属配位键在内的环化修饰技术，以提高肽的稳定性、生物利用度和靶标结合亲和力。本综述研究了环化修饰在抗病毒肽开发中的应用，重点关注靶向病毒融合和进入机制的环化肽，强调了它们对HSV和流感等嗜神经病毒的潜在作用。通过整合环化修饰赋予的结构刚性，这些构建体有望克服递送障碍并实现卓越的抗病毒疗效。本文通过强调抗病毒治疗的最新进展，突出了肽环化修饰的关键作用，并为未来多功能环化肽的研究提供了路线图。
