Yadav Shailendra, Kuldeep Jitendra, Siddiqi Mohammad I, Goyal Neena
Biochemistry Division, CSIR Central Drug Research Institute, Lucknow, India.
Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Antimicrob Agents Chemother. 2020 Jul 22;64(8). doi: 10.1128/AAC.00669-20.
T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In , the γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding. In the present study, we evaluated the essentiality of the LdTCP1γ gene. Gene replacement studies indicated that LdTCP1γ is essential for parasite survival. The LdTCP1γ single-allele-replacement mutants exhibited slowed growth and decreased infectivity in mouse macrophages compared to the growth and infectivity of the wild-type parasites. Modulation of LdTCP1γ expression in promastigotes also modulated cell cycle progression. Suramin, an antitrypanosomal drug, not only inhibited the luciferase refolding activity of the recombinant LdTCP1γ (rLdTCP1γ) homo-oligomeric complex but also exhibited potential antileishmanial efficacy both and The interaction of suramin and LdTCP1γ was further validated by isothermal titration calorimetry. The study suggests LdTCP1γ as a potential drug target and also provides a framework for the development of a new class of drugs.
T 复合体蛋白 1（TCP1）是一种普遍存在的 II 型伴侣蛋白，已知可折叠多种蛋白质，如肌动蛋白和微管蛋白。在[具体文献或研究中]，TCP1 的γ亚基（LdTCP1γ）已被克隆并鉴定。它形成一种高分子量的同源寡聚复合体，可进行依赖 ATP 的蛋白质折叠。在本研究中，我们评估了 LdTCP1γ基因的必要性。基因替换研究表明，LdTCP1γ对寄生虫的存活至关重要。与野生型寄生虫的生长和感染性相比，LdTCP1γ单等位基因替换突变体在小鼠巨噬细胞中生长缓慢且感染性降低。前鞭毛体中 LdTCP1γ表达的调节也调节了细胞周期进程。苏拉明是一种抗锥虫药物，不仅抑制重组 LdTCP1γ（rLdTCP1γ）同源寡聚复合体的荧光素酶重折叠活性，而且在[具体情况1]和[具体情况2]中均表现出潜在的抗利什曼原虫功效。通过等温滴定量热法进一步验证了苏拉明与 LdTCP1γ的相互作用。该研究表明 LdTCP1γ是一个潜在的药物靶点，也为开发新型药物提供了一个框架。
