Molecular Informatics and Design Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
Malaria Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
Acta Biomater. 2019 Mar 15;87:130-139. doi: 10.1016/j.actbio.2019.01.036. Epub 2019 Jan 18.
Lack of cell-type specificity and proteolytic susceptibility have long been the major bottlenecks for the development of peptide-based biomaterials for targeted drug delivery. Though a poly-l backbone provides the adaptability to re-conform the peptide structure to bind to a receptor, it also makes the peptide more susceptible to proteolytic cleavage. We have attempted to address this issue by designing a set of syndiotactic peptides de novo, with alternating l- and d-amino acids in succession. The designed peptides have higher rates of cellular uptake than the Tat (48-60) peptide in breast and cervical cancer cells. The uptake is independent of concentration, temperature and endocytosis (clathrin mediated). Importantly, the peptides are stable in both human plasma and bovine serum. The peptide-drug conjugates are much less toxic to the non-cancerous cells than cancer cells. The designed peptides are a step forward towards the development of targeted drug delivery vectors on peptide templates. STATEMENT OF SIGNIFICANCE: Present options in chemotherapy have multiple side effects arising from the lack of cell-type specificity, which makes them synonymous with "a Pyrrhic victory". Proteolytic susceptibility and non-specificity towards cancer cells has stunted the development of peptide-based biomaterials for targeted drug delivery. We have designed a set of peptides, addressing the above-mentioned roadblocks at an in vitro level. The peptides were designed on the template of a naturally existing peptide antibiotic from Bacillus brevis. The designed peptides have higher rates of cellular transduction than the model peptide (Tat), and is majorly membrane based. The peptides are stable in serum and selective towards cancer cells. Observations presented in this work can potentially take the discipline of de novo design of biomaterial conjugates forward.
肽基生物材料在靶向药物输送中的应用一直受到缺乏细胞类型特异性和蛋白水解易感性的限制。虽然聚 L 主链提供了适应性，可以重新构象肽结构以结合受体，但它也使肽更容易受到蛋白水解切割。我们试图通过设计一组交替的 L-和 D-氨基酸的全同立构肽来解决这个问题。与乳腺癌和宫颈癌细胞中的 Tat（48-60）肽相比，设计的肽具有更高的细胞摄取率。摄取与浓度、温度和内吞作用（网格蛋白介导）无关。重要的是，肽在人血浆和牛血清中都很稳定。肽-药物缀合物对非癌细胞的毒性比癌细胞低得多。与癌细胞相比，设计的肽在肽模板上向靶向药物输送载体的发展迈进了一步。
目前的化疗选择存在多种副作用，这些副作用源于缺乏细胞类型特异性，这使得它们等同于“得不偿失的胜利”。蛋白水解易感性和对癌细胞的非特异性阻碍了肽基生物材料在靶向药物输送中的发展。我们在体外水平上设计了一组肽，解决了上述障碍。这些肽是在来自短芽孢杆菌的天然存在的肽抗生素模板的基础上设计的。与模型肽（Tat）相比，设计的肽具有更高的细胞转导率，主要是基于膜的。肽在血清中稳定，对癌细胞具有选择性。本工作中的观察结果可能会推动生物材料缀合物的从头设计领域向前发展。
