Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease SUB1.
Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease SUB1.
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DOI：
10.1073/pnas.2022696118
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发表时间：
2021-05-18
影响因子：
11.1
通讯作者：
Jirgensons A
中科院分区：
文献类型：
--
作者：
Lidumniece E;Withers-Martinez C;Hackett F;Collins CR;Perrin AJ;Koussis K;Bisson C;Blackman MJ;Jirgensons A
疟疾仍然是一个重大的全球健康威胁。面对对现有化疗药物的耐药性不断增加的情况，迫切需要具有新作用模式的新抗疟药物。疟疾的病原体是一种单细胞寄生虫，侵入红细胞并在红细胞内复制。从红细胞中逃逸，这个过程被称为出口，涉及由一种称为SUB1的必需寄生虫枯草杆菌蛋白酶样丝氨酸蛋白酶触发的蛋白水解途径。在这里，我们描述了一种有效的、基于膜可渗透基质的硼酸化合物的开发和合理优化，该化合物通过直接抑制SUB1活性来阻止寄生虫的逸出和繁殖。这些化合物可以成为新型抗疟疾药物的基础，既可以防止感染又可以治疗疾病。疟疾是一种毁灭性的传染病，每年造成40多万人死亡，影响到世界近一半人口的生活。病原体，一种原生动物寄生虫，在红细胞（RBC）内复制，最终在称为出口的溶解过程中破坏细胞，释放新一代寄生虫。这些侵入新鲜的红细胞重复循环。出口是由一个重要的寄生虫枯草杆菌蛋白酶样丝氨酸蛋白酶称为SUB1。在这里，我们描述了基于底物的肽硼酸的开发和优化，以低纳摩尔效力抑制恶性疟原虫SUB1。结构优化产生了膜可渗透的、缓慢解离速率的抑制剂，其通过直接抑制SUB1活性来防止恶性疟原虫外出，并在亚微摩尔浓度下在体外阻断寄生虫复制。我们的研究结果验证了SUB1作为一类新的抗疟药物的潜在靶点，旨在防止寄生虫复制和疾病进展。
Malaria remains a major global health threat. In the face of increasing resistance to available chemotherapeutics, new antimalarial drugs with new modes of action are urgently needed. The causative agent of malaria is a single-celled parasite that invades and replicates within red blood cells. Escape from the red cell, a process called egress, involves a proteolytic pathway triggered by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and rational optimization of a potent, membrane-permeable substrate-based boronic acid compounds that block egress and parasite proliferation by direct inhibition of SUB1 activity. The compounds could form the basis of a new type of antimalarial medicine that would both protect against infection and treat disease. Malaria is a devastating infectious disease, which causes over 400,000 deaths per annum and impacts the lives of nearly half the world’s population. The causative agent, a protozoan parasite, replicates within red blood cells (RBCs), eventually destroying the cells in a lytic process called egress to release a new generation of parasites. These invade fresh RBCs to repeat the cycle. Egress is regulated by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and optimization of substrate-based peptidic boronic acids that inhibit Plasmodium falciparum SUB1 with low nanomolar potency. Structural optimization generated membrane-permeable, slow off-rate inhibitors that prevent P. falciparum egress through direct inhibition of SUB1 activity and block parasite replication in vitro at submicromolar concentrations. Our results validate SUB1 as a potential target for a new class of antimalarial drugs designed to prevent parasite replication and disease progression.
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加工恶性疟原虫梅罗唑群体表面蛋白MSP1激活谱线结合功能，从而使RBC的寄生虫出口。
影响因子：
30.3
作者：
Das S;Hertrich N;Perrin AJ;Withers-Martinez C;Collins CR;Jones ML;Watermeyer JM;Fobes ET;Martin SR;Saibil HR;Wright GJ;Treeck M;Epp C;Blackman MJ
通讯作者：
Blackman MJ
影响因子：
6.7
作者：
Collins CR;Hackett F;Strath M;Penzo M;Withers-Martinez C;Baker DA;Blackman MJ
通讯作者：
Blackman MJ
影响因子：
16.6
作者：
Baker DA;Stewart LB;Large JM;Bowyer PW;Ansell KH;Jiménez-Díaz MB;El Bakkouri M;Birchall K;Dechering KJ;Bouloc NS;Coombs PJ;Whalley D;Harding DJ;Smiljanic-Hurley E;Wheldon MC;Walker EM;Dessens JT;Lafuente MJ;Sanz LM;Gamo FJ;Ferrer SB;Hui R;Bousema T;Angulo-Barturén I;Merritt AT;Croft SL;Gutteridge WE;Kettleborough CA;Osborne SA
通讯作者：
Osborne SA
DOI：
10.1126/science.aaf8675
发表时间：
2017-10-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Pino P;Caldelari R;Mukherjee B;Vahokoski J;Klages N;Maco B;Collins CR;Blackman MJ;Kursula I;Heussler V;Brochet M;Soldati-Favre D
通讯作者：
Soldati-Favre D
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M