Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
Marshall Centre for Infectious Diseases Research and Training, School of Biomedical Sciences, University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.
ACS Infect Dis. 2024 Oct 11;10(10):3681-3691. doi: 10.1021/acsinfecdis.4c00553. Epub 2024 Oct 2.
Since Chagas disease, melioidosis, and Legionnaires' disease are all potentially life-threatening infections, there is an urgent need for new treatment strategies. All causative agents, , , and , express a virulence factor, the macrophage infectivity potentiator (MIP) protein, emerging as a promising new therapeutic target. Inhibition of MIP proteins having a peptidyl-prolyl isomerase activity leads to reduced viability, proliferation, and cell invasion. The affinity of a series of pipecolic acid-type MIP inhibitors was evaluated against all MIPs using a fluorescence polarization assay. The analysis of structure-activity relationships led to highly active inhibitors of MIPs of all pathogens, characterized by a one-digit nanomolar affinity for the MIPs and a very effective inhibition of their peptidyl-prolyl isomerase activity. Docking studies, molecular dynamics simulations, and quantum mechanical calculations suggest an extended σ-hole of the -halogenated phenyl sulfonamide to be responsible for the high affinity.
由于恰加斯病、类鼻疽和军团病都是潜在的危及生命的感染，因此迫切需要新的治疗策略。所有病原体， ， ， 和 ，都表达一种毒力因子，即巨噬细胞感染增强因子（MIP）蛋白，这是一个很有前途的新治疗靶点。抑制具有肽基脯氨酰顺反异构酶活性的 MIP 蛋白会导致活力、增殖和细胞侵袭减少。使用荧光偏振测定法评估了一系列哌啶酸型 MIP 抑制剂对所有 MIP 的亲和力。结构-活性关系的分析导致了所有病原体 MIP 的高活性抑制剂，其特征是对 MIP 的亲和力为纳摩尔级，对其肽基脯氨酰顺反异构酶活性的抑制非常有效。对接研究、分子动力学模拟和量子力学计算表明，-卤代苯磺酰胺的扩展 σ-空穴是导致高亲和力的原因。
