Grover Ankita, Singh Sawraj, Sindhu Sonal, Lath Amit, Kumar Sanjay
Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, 124001, India.
Department of Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India.
Mol Divers. 2025 Jan 25. doi: 10.1007/s11030-025-11113-w.
Cyclotides are a class of plant-derived cyclic peptides having a distinctive structure with a cyclic cystine knot (CCK) motif. They are stable molecules that naturally play a role in plant defense. Till date, more than 750 cyclotides have been reported among diverse plant taxa belonging to Cucurbitaceae, Violaceae, Rubiaceae, Solanaceae, and Fabaceae. These native cyclotides exhibit several bioactivities, such as anti-bacterial, anti-HIV, anti-fungal, pesticidal, cytotoxic, and hemolytic activities which have immense significance in agriculture and therapeutics. The general mode of action of cyclotides is related to their structure, where their hydrophobic face penetrates the cell membrane and disrupts it to exhibit anti-microbial, cytotoxic, or hemolytic activities. Thus, the structure-activity relationship is of significance in cyclotides. Further, owing to their, small size, stability, and potential to interact and cross the membrane barrier of cells, they make promising choices for developing peptide-based biologics. However, challenges, such as production complexity, pharmacokinetic limitations, and off-target effects hinder their development. Advancements in cyclotide engineering, such as peptide grafting, ligand conjugation, and nanocarrier integration, heterologous production along with computational design optimization, can help overcome these challenges. Given the potential of these cyclic peptides, the present review focuses on the diversity, bioactivities, and structure-activity relationships of cyclotides, and advancements in cyclotides engineering emphasizing their unique attributes for diverse medical and biotechnological applications.
环肽是一类植物源环肽，具有独特的结构，带有环胱氨酸结（CCK）基序。它们是稳定的分子，在植物防御中自然发挥作用。迄今为止，在葫芦科、堇菜科、茜草科、茄科和豆科等不同植物类群中已报道了750多种环肽。这些天然环肽具有多种生物活性，如抗菌、抗HIV、抗真菌、杀虫、细胞毒性和溶血活性，在农业和治疗领域具有重要意义。环肽的一般作用方式与其结构有关，其疏水面穿透细胞膜并使其破坏，从而表现出抗微生物、细胞毒性或溶血活性。因此，环肽的构效关系具有重要意义。此外，由于它们体积小、稳定性好，以及具有与细胞的膜屏障相互作用并穿过膜屏障的潜力，它们为开发基于肽的生物制剂提供了有前景的选择。然而，生产复杂性、药代动力学限制和脱靶效应等挑战阻碍了它们的发展。环肽工程的进展，如肽嫁接、配体偶联和纳米载体整合、异源生产以及计算设计优化，有助于克服这些挑战。鉴于这些环肽的潜力，本综述重点关注环肽的多样性、生物活性和构效关系，以及环肽工程的进展，强调它们在各种医学和生物技术应用中的独特属性。
