Targeting Plasmodium with constrained peptides and peptidomimetics
Targeting Plasmodium with constrained peptides and peptidomimetics
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用限制肽和肽模拟物靶向疟原虫
DOI：
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
E. Kennedy
中科院分区：
文献类型：
--
作者：
Leah G. Helton;E. Kennedy
疟疾仍然是一个全球性的健康问题，估计每年有25亿人感染，近50万人死亡。疟疾是由疟原虫株的寄生虫感染引起的，疟原虫株从蚊子传播到人类宿主。尽管已经发现几种小分子抑制剂靶向传播的早期阶段并防止寄生虫增殖，但已经出现了多种耐药寄生虫菌株，耐药性仍然是一个主要障碍。作为小分子抑制的替代方案，已经探索了几种基于肽的治疗剂作为抗疟化合物的潜力。开发了化学约束肽或肽模拟物以靶向基于寄生虫的蛋白质的大结合界面，这些蛋白质在历史上难以使用小分子选择性抑制。在这里，我们回顾了正在进行的研究，旨在开发约束肽靶向蛋白质-蛋白质相互作用有关的疟疾发病机制。这些靶点包括Falcipain-2、CDPK 1的J结构域、肌球蛋白A尾结构域相互作用蛋白、PKA信号通路和涉及血管紧张素衍生肽的不清楚的信号通路。对于每个目标也使用了不同的合成方法。将寄生虫生物学与合成策略相结合可能为开发发现新型抗疟药物的替代方法提供新的机会，并可能为靶向耐药寄生虫菌株提供替代来源。
Malaria remains a worldwide health concern with an estimated quarter of a billion people infected and nearly half a million deaths annually. Malaria is caused by a parasite infection from Plasmodium strains which are transmitted from mosquitoes into the human host. Although several small molecule inhibitors have been found to target the early stages of transmission and prevent parasite proliferation, multiple drug resistant parasite strains have emerged and drug resistance remains a major hurdle. As an alternative to small molecule inhibition, several peptide‐based therapeutics have been explored for their potential as antimalarial compounds. Chemically constrained peptides or peptidomimetics were developed to target large binding interfaces of parasite‐based proteins that have historically been difficult to selectively inhibit using small molecules. Here, we review ongoing research aimed at developing constrained peptides targeting protein–protein interactions pertinent to malaria pathogenesis. These targets include Falcipain‐2, the J domain of CDPK1, myosin A tail domain interacting protein, the PKA signaling pathway, and an unclear signaling pathway involving angiotensin‐derived peptides. Diverse synthetic methods were also used for each target. Merging parasite biology with synthetic strategies may provide new opportunities to develop alternative methods for uncovering novel antimalarials and may offer an alternate source for targeting drug‐resistant parasite strains.
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恶性疟原虫：半胱氨酸蛋白酶 falcipain-2 的生化特征。
DOI：
10.1016/j.exppara.2005.10.007
发表时间：
2006
期刊：
Experimental parasitology.
影响因子：
--
作者：
Singh,Naresh;Sijwali,PuranS;Pandey,KailashC;Rosenthal,PhilipJ
通讯作者：
Rosenthal,PhilipJ
影响因子：
13.8
作者：
Esseltine, Jessica L.;Scott, John D.
通讯作者：
Scott, John D.
DOI：
10.1073/pnas.0600489103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Wang, Stephanie X.;Pandey, Kailash C.;McKerrow, James H.
通讯作者：
McKerrow, James H.
影响因子：
1.5
作者：
Dua, M;Raphael, P;Hanspal, M
通讯作者：
Hanspal, M
影响因子：
16.6
作者：
Solyakov, Lev;Halbert, Jean;Doerig, Christian
通讯作者：
Doerig, Christian