Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis.
Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis.
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DOI：
10.1371/journal.pone.0193982
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Reed SL
中科院分区：
文献类型：
--
作者：
Chaparro JD;Cheng T;Tran UP;Andrade RM;Brenner SBT;Hwang G;Cohn S;Hirata K;McKerrow JH;Reed SL
Although toxoplasmosis is one of the most common parasitic infections worldwide, therapeutic options remain limited. Cathepsins, proteases that play key roles in the pathogenesis of toxoplasmosis and many other protozoan infections, are important potential therapeutic targets. Because both TgCPB and TgCPL play a role in T. gondii invasion, we evaluated the efficacy of the potent, irreversible vinyl sulfone inhibitor, K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl). The inhibitor’s toxicity and pharmacokinetic profile have been well-studied because of its in vitro and in vivo activity against a number of parasites. We found that it inhibited both TgCPB (EC50 = 114 nM) and TgCPL (EC50 = 71 nM) in vitro. K11777 also inhibited invasion of human fibroblasts by RH tachyzoites by 71% (p = 0.003) and intracellular replication by >99% (p<0.0001). In vivo, a single dose of K11777 led to 100% survival of chicken embryos in an model of acute toxoplasmosis (p = 0.015 Cox regression analysis). Therefore, K11777 shows promise as a novel therapeutic agent in the treatment of toxoplasmosis, and may prove to be a broadly effective anti-parasitic agent.
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影响因子：
1.5
作者：
Huang, Robert;Que, Xuchu;Hirata, Ken;Brinen, Linda S.;Lee, Ji Hyun;Hansell, Elizabeth;Engel, Juan;Sajid, Mohammed;Reed, Sharon
通讯作者：
Reed, Sharon
影响因子：
15.8
作者：
Abdulla MH;Lim KC;Sajid M;McKerrow JH;Caffrey CR
通讯作者：
Caffrey CR
影响因子：
3.1
作者：
Que, XC;Wunderlich, A;Reed, SL
通讯作者：
Reed, SL
影响因子：
4.8
作者：
O'Brien, Theresa C.;Mackey, Zachary B.;McKerrow, James H.
通讯作者：
McKerrow, James H.
影响因子：
6.4
作者：
KENNEDY, CA;PIMENTEL, JA;OLDFIELD, EC
通讯作者：
OLDFIELD, EC