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)
|
Text
116340.pdf - Published Version Available under License Creative Commons Attribution. 817kB |
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, Professor 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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric