摘要
The underdevelopment of adjuvant discovery and diversity, compared to core vaccine technology, is evident. On the other hand, antibiotic resistance is on the list of the top ten threats to global health. Immunomodulatory peptides that target a pathogen and modulate the immune system simultaneously are promising for the development of preventive and therapeutic molecules. Since investigating innate immunity in insects has led to prominent achievements in human immunology, such as toll-like receptor (TLR) discovery, we used the capacity of the immunomodulatory peptides of arthropods with concomitant antimicrobial or antitumor activity. An SVM-based machine learning classifier identified short immunomodulatory sequences encrypted in 643 antimicrobial peptides from 55 foe-to-friend arthropods. The critical features involved in efficacy and safety were calculated. Finally, 76 safe immunomodulators were identified. Then, molecular docking and simulation studies defined the target of the most optimal peptide ligands among all human cell-surface TLRs. SPalf2-453 from a crab is a cell-penetrating immunoadjuvant with antiviral properties. The peptide interacts with the TLR1/2 heterodimer. SBsib-711 from a blackfly is a TLR4/MD2 ligand used as a cancer vaccine immunoadjuvant. In addition, SBsib-711 binds CD47 and PD-L1 on tumor cells, which is applicable in cancer immunotherapy as a checkpoint inhibitor. MRh4-679 from a shrimp is a broad-spectrum or universal immunoadjuvant with a putative Th1/Th2-balanced response. We also implemented a pathway enrichment analysis to define fingerprints or immunological signatures for further in vitro and in vivo immunogenicity and reactogenicity measurements. Conclusively, combinatorial machine learning, molecular docking, and simulation studies, as well as systems biology, open a new opportunity for the discovery and development of multifunctional prophylactic and therapeutic lead peptides.
摘要译文
与核心疫苗技术相比，辅助发现和多样性的不足是显而易见的。另一方面，抗生素耐药性排在对全球健康的十大威胁列表中。靶向病原体并同时调节免疫系统的免疫调节肽有望开发预防和治疗分子。自从研究昆虫的先天免疫力已导致人类免疫学上的显着成就，例如Toll样受体（TLR）发现，我们使用了节肢动物的免疫调节肽具有伴侣抗菌或抗肿瘤活性的能力。基于SVM的机器学习分类器确定了来自55个敌人到朋友节肢动物的643种抗菌肽中的简短免疫调节序列。计算了功效和安全性涉及的关键特征。最后，确定了76个安全的免疫调节剂。然后，分子对接和模拟研究定义了所有人类细胞表面TLR中最佳肽配体的靶标。来自螃蟹的Spalf2-453是具有抗病毒特性的细胞穿透免疫辅助。肽与TLR1/2异二聚体相互作用。Blackfly的SBSIB-711是TLR4/MD2配体用作癌症疫苗免疫辅助剂。此外，SBSIB-711在肿瘤细胞上结合CD47和PD-L1，该细胞适用于癌症免疫疗法作为检查点抑制剂。来自虾的MRH4-679是具有推定的Th1/Th2平衡反应的广谱或普遍免疫辅助。我们还实施了途径富集分析，以定义指纹或免疫信号，以进一步体外和体内免疫原性和反应生成性测量。结论性地，组合机器学习，分子对接和模拟研究以及系统生物学为发现和开发多功能预防性和治疗性铅肽打开了新的机会。
Shiva Hemmati (0000-0001-9071-9569) [1];Zahra Saeidikia [2];Hassan Seradj [3];Abdolali Mohagheghzadeh [4];. Immunomodulatory Peptides as Vaccine Adjuvants and Antimicrobial Agents[J]. Pharmaceuticals, 2024,17(2): 201