Stephanie Filia, Saragih Mutiara, Tambunan Usman Sumo Friend, Siahaan Teruna J
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Jawa Barat 16424, Indonesia.
Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS 66045, USA.
Life (Basel). 2022 Aug 28;12(9):1333. doi: 10.3390/life12091333.
Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Although several established antitubercular drugs have been found, various factors obstruct efforts to combat this disease due to the existence of drug-resistance (DR) TB strains, the need for lengthy treatment, and the occurrence of side effects from drug-drug interactions. Rifampicin (RIF) is the first line of antitubercular drugs and targets RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). Here, RIF blocks the synthesis of long RNA during transcription initiation. The efficacy of RIF is low in DR-TB strains, and the use of RIF leads to various side effects. In this study, novel cyclic peptides were computationally designed as inhibitors of MTB transcription initiation. The designed cyclic peptides were subjected to a virtual screening to generate compounds that can bind to the RIF binding site in MTB RNAP subunit β (RpoB) for obtaining a new potential TB drug with a safe clinical profile. The molecular simulations showed that the cyclic peptides were capable of binding with RpoB mutants, suggesting that they can be possibility utilized for treating DR-TB. Structural modifications were carried out by acetylation and amidation of the N- and C-terminus, respectively, to improve their plasma stability and bioavailability. The modified linear and cyclic peptides were successfully synthesized with a solid-phase peptide synthesis method using Fmoc chemistry, and they were characterized by analytical HPLC, LC-ESI-MS, and 1H NMR.
结核病（TB）仍然是世界上最致命的传染病之一。尽管已经发现了几种既定的抗结核药物，但由于耐药性（DR）结核菌株的存在、需要长期治疗以及药物相互作用产生的副作用，各种因素阻碍了对抗这种疾病的努力。利福平（RIF）是一线抗结核药物，靶向结核分枝杆菌（MTB）的RNA聚合酶（RNAP）。在这里，RIF在转录起始过程中阻断长链RNA的合成。RIF在DR-TB菌株中的疗效较低，并且使用RIF会导致各种副作用。在本研究中，通过计算设计新型环肽作为MTB转录起始的抑制剂。对设计的环肽进行虚拟筛选，以生成能够与MTB RNAP亚基β（RpoB）中的RIF结合位点结合的化合物，从而获得具有安全临床特征的新型潜在抗结核药物。分子模拟表明，环肽能够与RpoB突变体结合，表明它们有可能用于治疗DR-TB。分别通过N端和C端的乙酰化和酰胺化进行结构修饰，以提高其血浆稳定性和生物利用度。使用Fmoc化学方法通过固相肽合成法成功合成了修饰的线性和环肽，并通过分析型HPLC、LC-ESI-MS和1H NMR对其进行了表征。
