期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 59, 期 11, 页码 6708-6716出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00596-15
关键词
-
资金
- Wellcome Trust [085349]
- Wellcome Trust Institutional Strategic Support Fund [097821/Z/11/Z]
- Netherlands Organization for Scientific Research
- government of Saudi Arabia
- Tertiary Education TRUST Fund, Abuja, Nigeria
- Biotechnology and Biological Sciences Research Council [BB/K006495/1] Funding Source: researchfish
- BBSRC [BB/K006495/1] Funding Source: UKRI
The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing group, and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine (compound 1) as a new lead compound, which showed submicromolar potency against Trypanosoma brucei, with a selectivity index of >500, and it demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of action of this lead compound and showed that this molecule has significantly higher affinity for parasites over mammalian nucleobase transporters, and it does not show cross-resistance with current first-line drugs. Once selectively accumulated inside the parasite, the prodrug releases a DNA-damaging methyldiazonium cation. We propose that ensuing futile cycles of attempted mismatch repair then lead to G(2)/M phase arrest and eventually cell death, as evidenced by the reduced efficacy of this purine analog against a mismatch repair-deficient (MSH2(-/-)) trypanosome cell line. The observed absence of genotoxicity, hepatotoxicity, and cytotoxicity against mammalian cells revitalizes the idea of pursuing parasite- selective DNA alkylators as a safe chemotherapeutic option for the treatment of human and animal trypanosomiasis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据