Sharma Krishna K, Maurya Indresh Kumar, Khan Shabana I, Jacob Melissa R, Kumar Vinod, Tikoo Kulbhushan, Jain Rahul
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research , Sector 67, S. A. S. Nagar, Punjab 160 062, India.
Department of Microbial Biotechnology, Panjab University , Sector 25, Chandigarh, 160 014, India.
J Med Chem. 2017 Aug 10;60(15):6607-6621. doi: 10.1021/acs.jmedchem.7b00481. Epub 2017 Jul 25.
The new structural classes of ultrashort peptides that exhibit potent microbicidal action have potential as future drugs. Herein, we report that C-2 arylated histidines containing tripeptides His(2-Ar)-Trp-His(2-Ar) exhibit potent antifungal activity against Cryptococcus neoformans with high selectivity. The most potent peptide 12f [His(2-biphenyl)-Trp-His(2-biphenyl)] displayed high in vitro activity against C. neoformans (IC = 0.35 μg/mL, MIC = MFC = 0.63 μg/mL) with a selectivity index of >28 and 2 times higher potency compared to amphotericin B. Peptide 12f exhibited proteolytic stability, with no apparent hemolytic activity. The mechanism of action study of 12f by confocal laser scanning microscopy and electron microscopy indicates nuclear fragmentation and membrane disruption of C. neoformans cells. Combinations of 12f with fluconazole and amphotericin B at subinhibitory concentration were synergistic against C. neoformans. This study suggests that 12f is a new structural class of amphiphilic peptide with rapid fungicidal activity caused by C. neoformans.
具有强大杀菌作用的新型超短肽结构类群具有作为未来药物的潜力。在此，我们报告含有三肽His(2-Ar)-Trp-His(2-Ar)的C-2芳基化组氨酸对新型隐球菌具有强大的抗真菌活性且选择性高。最有效的肽12f [His(2-联苯)-Trp-His(2-联苯)]对新型隐球菌显示出高体外活性(IC = 0.35 μg/mL，MIC = MFC = 0.63 μg/mL)，选择性指数>28，效力是两性霉素B的2倍。肽12f表现出蛋白水解稳定性，无明显溶血活性。通过共聚焦激光扫描显微镜和电子显微镜对12f的作用机制研究表明新型隐球菌细胞出现核碎片化和膜破坏。12f与亚抑制浓度的氟康唑和两性霉素B联合使用对新型隐球菌具有协同作用。本研究表明12f是一种新型两亲性肽结构类群，对新型隐球菌具有快速杀菌活性。
