Abstract：
Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto β7. Inhibition of Pfβ5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the β5/β6/β3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.
摘要：
疟疾仍然是全球健康问题，因为耐药性威胁着治疗计划。我们通过表型筛选鉴定了具有抗疟疾活性的哌啶甲酰胺(SW042)。对SW042抗性恶性疟原虫（Pf）寄生虫的选择揭示了Pf_蛋白酶体β5活性位点（Pfβ5）的点突变。口服给药后，有效的类似物（SW584）在人疟疾小鼠模型中显示出功效。SW584具有低的产生抗性的倾向(抗性的最小接种物[MIR]>109)并且与双氢青蒿素协同。通过将His8标签引入到β7上促进了Pf_蛋白酶体的纯化。Pfβ5的抑制与寄生虫杀伤有关，不抑制人蛋白酶体同工型或显示细胞毒性。Pf_proteasome_SW584低温电子显微镜（cryo-EM）结构显示SW584与催化苏氨酸非共价结合，在β5/β6/β3亚基界面的未探索口袋中，Pf和人蛋白酶体之间存在物种差异。识别一个可逆的，物种选择性，具有低耐药倾向的口服活性系列为这一基本目标的药物治疗提供了途径。
