De Cena Gabrielle Lupeti, Scavassa Bruna Vitória, Conceição Katia
Laboratory of Peptide Biochemistry, Universidade Federal de São Paulo (UNIFESP), São José dos Campos 12231-280, Brazil.
Pharmaceuticals (Basel). 2022 Sep 13;15(9):1141. doi: 10.3390/ph15091141.
The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug delivery systems, respectively. This study used in silico methods to predict AMPs and CPPs derived from natterins from the venomous fish . Fifty-seven BAPs (19 AMPs, 8 CPPs, and 30 AMPs/CPPs) were identified using the web servers CAMP, AMPA, AmpGram, C2Pred, and CellPPD. The physicochemical properties were analyzed using ProtParam, PepCalc, and DispHred tools. The membrane-binding potential and cellular location of each peptide were analyzed using the Boman index by APD3, and TMHMM web servers. All CPPs and two AMPs showed high membrane-binding potential. Fifty-four peptides were located in the plasma membrane. Peptide immunogenicity, toxicity, allergenicity, and ADMET parameters were evaluated using several web servers. Sixteen antiviral peptides and 37 anticancer peptides were predicted using the web servers Meta-iAVP and ACPred. Secondary structures and helical wheel projections were predicted using the PEP-FOLD3 and Heliquest web servers. Fifteen peptides are potential lead compounds and were selected to be further synthesized and tested experimentally in vitro to validate the in silico screening. The use of computer-aided design for predicting peptide structure and activity is fast and cost-effective and facilitates the design of potent therapeutic peptides. The results demonstrate that toxins form a natural biotechnological platform in drug discovery, and the presence of CPP and AMP sequences in toxin families opens new possibilities in toxin biochemistry research.
毒液衍生肽，如生物活性肽（BAPs）的治疗潜力，取决于其特异性、稳定性和药代动力学特性。BAPs包括抗感染或抗菌肽（AMPs）和细胞穿透肽（CPPs），它们具有若干物理化学特性，分别是基于抗生素的治疗方法和药物递送系统的潜在替代品。本研究采用计算机模拟方法预测来自有毒鱼类的纳氏毒素衍生的AMPs和CPPs。使用网络服务器CAMP、AMPA、AmpGram、C2Pred和CellPPD鉴定出57种BAPs（19种AMPs、8种CPPs和30种AMPs/CPPs）。使用ProtParam、PepCalc和DispHred工具分析其物理化学性质。使用APD3的博曼指数和TMHMM网络服务器分析每种肽的膜结合潜力和细胞定位。所有CPPs和两种AMPs均显示出高膜结合潜力。54种肽位于质膜中。使用多个网络服务器评估肽的免疫原性、毒性、致敏性和ADMET参数。使用网络服务器Meta-iAVP和ACPred预测出16种抗病毒肽和37种抗癌肽。使用PEP-FOLD3和Heliquest网络服务器预测二级结构和螺旋轮投影。15种肽是潜在的先导化合物，被选择进一步合成并在体外进行实验测试，以验证计算机模拟筛选结果。利用计算机辅助设计预测肽的结构和活性快速且具有成本效益，有助于设计有效的治疗性肽。结果表明，毒素在药物发现中形成了一个天然的生物技术平台，毒素家族中CPP和AMP序列的存在为毒素生物化学研究开辟了新的可能性。
