Torres Marcelo D T, Silva Adriana F, Andrade Gislaine P, Pedron Cibele N, Cerchiaro Giselle, Ribeiro Anderson O, Oliveira Vani X, de la Fuente-Nunez Cesar
Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Penn Institute for Computational Science, and Department of Bioengineering University of Pennsylvania Philadelphia Pennsylvania USA.
Centro de Ciências Naturais e Humanas Universidade Federal do ABC Santo André SP Brazil.
Bioeng Transl Med. 2020 Jun 5;5(3):e10167. doi: 10.1002/btm2.10167. eCollection 2020 Sep.
The wasp venom-derived antimicrobial peptide polybia-CP has been previously shown to exhibit potent antimicrobial activity, but it is also highly toxic. Previously, using a physicochemical-guided peptide design strategy, we reversed its toxicity while preserving and even enhancing its antibacterial properties. Here, we report on several additional unanticipated biological properties of polybia-CP and derivatives, namely their ability to target and cancer cells. We leverage a physicochemical-guided approach to identify features that operate as functional hotspots making these peptides viable antiplasmodial and anticancer agents. Helical content and net positive charge are identified as key structural and physicochemical determinants for antiplasmodial activity. In addition to helicity and net charge, hydrophobicity-related properties of polybia-CP and derivatives were found to be equally critical to target cancer cells. We demonstrate that by tuning these physicochemical parameters, it is possible to design synthetic peptides with enhanced submicromolar antiplasmodial potency and micromolar anticancer activity. This study reveals novel and previously undescribed functions for Polybia-CP and analogs. Additionally, we demonstrate that a physicochemical-guided rational design strategy can be used for identifying functional hotspots in peptide molecules and for tuning structure-function to generate novel and potent new-to-nature therapies.
黄蜂毒液来源的抗菌肽多比亚-CP先前已被证明具有强大的抗菌活性，但它也具有高毒性。此前，我们采用物理化学指导的肽设计策略，在保留甚至增强其抗菌特性的同时逆转了其毒性。在此，我们报告多比亚-CP及其衍生物的其他一些意外生物学特性，即它们靶向癌细胞的能力。我们利用物理化学指导的方法来识别作为功能热点起作用的特征，使这些肽成为可行的抗疟和抗癌剂。螺旋含量和净正电荷被确定为抗疟活性的关键结构和物理化学决定因素。除了螺旋度和净电荷外，多比亚-CP及其衍生物的与疏水性相关的特性对于靶向癌细胞同样至关重要。我们证明，通过调整这些物理化学参数，可以设计出具有增强的亚微摩尔抗疟效力和微摩尔抗癌活性的合成肽。这项研究揭示了多比亚-CP及其类似物的新的和以前未描述的功能。此外，我们证明物理化学指导的合理设计策略可用于识别肽分子中的功能热点，并用于调整结构-功能以产生新的、有效的新型天然疗法。
