Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials.
Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials.
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DOI：
10.1016/j.chom.2012.10.017
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发表时间：
2012-12-13
影响因子：
30.3
通讯作者：
Greenbaum DC
中科院分区：
文献类型：
--
作者：
Love MS;Millholland MG;Mishra S;Kulkarni S;Freeman KB;Pan W;Kavash RW;Costanzo MJ;Jo H;Daly TM;Williams DR;Kowalska MA;Bergman LW;Poncz M;DeGrado WF;Sinnis P;Scott RW;Greenbaum DC
恶性疟原虫的发病机制受到血液中多种细胞类型的影响，其中包括可以杀死红细胞内疟原虫的血小板。血小板可以通过人类防御肽（HDP）介导这些抗疟作用，HDP通过透化膜发挥抗菌作用。因此，我们筛选了一组 HDP，并确定人血小板因子 4 (hPF4) 通过选择性裂解寄生虫消化液泡 (DV) 来杀死红细胞内的疟疾寄生虫。 PF4 仅在受感染的红细胞内快速积累，并且是在受感染的红细胞-血小板共培养物中杀死寄生虫所必需的。为了利用这种抗疟机制，我们测试了一个小型非肽类 HDP 模拟物 (smHDP) 库，并鉴定出通过快速裂解寄生虫 DV 同时不伤害红细胞质膜来杀死恶性疟原虫的化合物。铅 smHDP 还可以减少小鼠疟疾模型中的寄生虫血症。因此，识别控制寄生虫生长的宿主分子可以进一步开发具有治疗潜力的相关分子。
Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential.
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影响因子：
30.3
作者：
Srivastava, Kalyan;Cockburn, Ian A;Swaim, AnneMarie;Thompson, Laura E;Tripathi, Abhai;Fletcher, Craig A;Shirk, Erin M;Sun, Henry;Kowalska, M Anna;Fox-Talbot, Karen;Sullivan, David;Zavala, Fidel;Morrell, Craig N
通讯作者：
Morrell, Craig N
影响因子：
3.7
作者：
Ortyn, William E.;Perry, David J.;Basiji, David A.
通讯作者：
Basiji, David A.
影响因子：
20.3
作者：
Eslin, DE;Zhang, CY;Kowalska, MA
通讯作者：
Kowalska, MA
影响因子：
6.4
作者：
Wassmer, Samuel Crocodile;Taylor, Terrie;Grau, Georges Emile
通讯作者：
Grau, Georges Emile
影响因子：
3.4
作者：
Yeaman, Michael R.;Yount, Nannette Y.;Welch, William H.
通讯作者：
Welch, William H.