Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Khare Shilpi; Nagle Advait S.; Biggart Agnes; Lai Yin H.; Liang Fang; Davis Lauren C.; Barnes S. Whitney; Mathison Casey J. N.; Myburgh Elmarie; Gao Mu-Yun; Gillespie J. Robert; Liu Xianzhong; Tan Jocelyn L.; Stinson Monique; Rivera Ianne C.; Ballard Jaime; Yeh Vince; Groessl Todd; Federe Glenn; Koh Hazel X. Y.; Venable John D.; Bursulaya Badry; Shapiro Michael; Mishra Pranab K.; Spraggon Glen; Brock Ansgar; Mottram Jeremy C.; Buckner Frederick S.; Rao Srinivasa P. S.; Wen Ben G.; Walker John R.; Tuntland Tove; Molteni Valentina; Glynne Richard J.; Supek Frantisek

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Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

机译：蛋白酶体抑制剂治疗利什曼病，查加斯病和昏睡病

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Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually(1). The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target(2). However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

机译：查加斯病，利什曼病和昏睡病影响全世界2000万人，每年导致50,000多人死亡（1）。该疾病是由运动型质体寄生虫克氏锥虫（Leishmania spp）感染引起的。和布鲁氏锥虫。这些寄生虫具有相似的生物学和基因组序列，表明可以通过调节保守的寄生虫靶标活性的药物治愈所有三种疾病（2）。但是，迄今尚未发现此类分子靶标或广谱药物。在这里，我们描述了具有空前的体内功效的动素体蛋白酶体（GNF6702）的选择性抑制剂，可在所有三种感染模型中从小鼠身上清除寄生虫。 GNF6702通过非竞争性机制抑制运动质体蛋白酶体，不抑制哺乳动物蛋白酶体或哺乳动物细胞的生长，并且在小鼠中具有良好的耐受性。我们的数据为寄生虫蛋白酶体的遗传和化学验证提供了有希望的治疗动素体感染的治疗靶标，并强调了开发针对这些被忽视疾病的单类药物的可能性。

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《Nature》 |2016年第7619期|229-233|共5页
作者
Khare Shilpi; Nagle Advait S.; Biggart Agnes; Lai Yin H.; Liang Fang; Davis Lauren C.; Barnes S. Whitney; Mathison Casey J. N.; Myburgh Elmarie; Gao Mu-Yun; Gillespie J. Robert; Liu Xianzhong; Tan Jocelyn L.; Stinson Monique; Rivera Ianne C.; Ballard Jaime; Yeh Vince; Groessl Todd; Federe Glenn; Koh Hazel X. Y.; Venable John D.; Bursulaya Badry; Shapiro Michael; Mishra Pranab K.; Spraggon Glen; Brock Ansgar; Mottram Jeremy C.; Buckner Frederick S.; Rao Srinivasa P. S.; Wen Ben G.; Walker John R.; Tuntland Tove; Molteni Valentina; Glynne Richard J.; Supek Frantisek;
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Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Wellcome Trust Ctr Mol Parasitol, Glasgow G12 8TA, Lanark, Scotland|Univ York, Dept Biol, Ctr Immunol & Infect, Wentworth Way, York YO10 5DD, N Yorkshire, England;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Univ Washington, Dept Med, Seattle, WA 98109 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Inst Trop Dis, 10 Biopolis Rd, Singapore 138670, Singapore;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Wellcome Trust Ctr Mol Parasitol, Glasgow G12 8TA, Lanark, Scotland|Univ York, Dept Biol, Ctr Immunol & Infect, Wentworth Way, York YO10 5DD, N Yorkshire, England;

Univ Washington, Dept Med, Seattle, WA 98109 USA;

Novartis Inst Trop Dis, 10 Biopolis Rd, Singapore 138670, Singapore;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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6. Proteasome inhibition for treatment of leishmaniasis Chagas disease and sleeping sickness [O] . Shilpi Khare, Advait S. Nagle, Agnes Biggart, -1

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Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

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