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.
Highlights
The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship
We present the development of purine derivatives that meet these requirements by carrying a methyltriazenyl toxophore on the purine 2 position. These methyltriazenyl purines (MTPs) constitute a class of highly effective antitrypanosomal agents. We propose that this therapeutic class of agents damages the DNA of the parasite, which results in futile cycling of the mismatch repair system, leading eventually to parasite cell death
Substrate recognition models that we previously published for this transporter class showed that the purine 2-position is not utilized in binding to trypanosomatid nucleobase transporters, whereas it is engaged in hydrogen bond formation in human nucleobase transporters [19, 27]
Summary
The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. We sought to rationally exploit a different set of high-affinity trypanosomal transporters, thereby ensuring rapid and selective accumulation of the agent within its target cell without building in cross-resistance to existing chemotherapy. T. brucei nucleobase transporters are proton symporters, meaning that they utilize the proton motive force across the plasma membrane to actively transport their substrate into the cell, even against a strong concentration gradient [17, 18] All this has the effect of rapidly and selectively pumping the active compound into the target cell and, as active transport is monodirectional, the substrate will not be able to egress from the cell in the same way [14]
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