Targeting the parasite's DNA with methyltriazenyl purine analogs Is a safe, selective, and efficacious antitrypanosomal strategy

Rodenko, B., Wanner, M., Alkhaldi, A., Ebiloma, G., Barnes, R., Kaiser, M., Brun, R., McCulloch, R. , Koomen, G.-J. and De Koning, H. P. (2015) Targeting the parasite's DNA with methyltriazenyl purine analogs Is a safe, selective, and efficacious antitrypanosomal strategy. Antimicrobial Agents and Chemotherapy, 59(11), pp. 6708-6716. (doi:10.1128/aac.00596-15) (PMID:26282430) (PMCID:PMC4604408)

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Abstract

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 G2/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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McCulloch, Dr Richard and De Koning, Professor Harry and Rodenko, Dr Boris
Authors: Rodenko, B., Wanner, M., Alkhaldi, A., Ebiloma, G., Barnes, R., Kaiser, M., Brun, R., McCulloch, R., Koomen, G.-J., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596
Copyright Holders:Copyright © 2015 Rodenko et al.
First Published:First published in Radiation Research 184(5):482-493
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
371791The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)073990/Z/03/ZIII - PARASITOLOGY
593571Manipulation of cancer cells by nanotopography: strategies to control migration, proliferation and apoptosis (ISSF Catalyst Fund)Penelope TsimbouriWellcome Trust (WELLCOME)097821/Z/11/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY