Targeting the parasite's DNA with methyltriazenyl purine analogs is a safe, selective, and efficacious antitrypanosomal strategy.
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.
College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom boris.rodenko@glasgow.ac.uk harry.de-koning@glasgow.ac.uk.
Boris
B
Rodenko
Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Martin J
MJ
Wanner
College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom Department of Biology, College of Science, Aljouf University, Skaka, Kingdom of Saudi Arabia.
Abdulsalam A M
AA
Alkhaldi
College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Godwin U
GU
Ebiloma
College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Rebecca L
RL
Barnes
Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
Marcel
M
Kaiser
Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
Reto
R
Brun
College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom.
Richard
R
McCulloch
Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Gerrit-Jan
GJ
Koomen
College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom boris.rodenko@glasgow.ac.uk harry.de-koning@glasgow.ac.uk.
Harry P
HP
de Koning
D000818:Animals; D002460:Cell Line; D016054:DNA, Protozoan / Q000187:drug effects / Q000235:genetics*; D005260:Female; D051379:Mice; D011687:Purines / Q000737:chemistry* / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000627:therapeutic use*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
D016054:DNA, Protozoan; D011687:Purines; D014344:Trypanocidal Agents; C030985:purine