Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin

Abstract

BackgroundThere is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).Methodology/Principal FindingsCordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug.Conclusions/SignificanceAltogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

Assessment of the burden of human African trypanosomiasis by rapid participatory appraisal in three high-risk villages in Urambo District, Northwest Tanzania

“…New second stage drugs are currently in development [22][23] but are unlikely to become available in the near future, so that reducing the burden of HAT in Urambo in the short-medium term will require a clear commitment to improving access to diagnostic and treatment services. The development of Loop-Mediated Isothermal Amplification (LAMP) diagnostic tests for HAT 24 , suitable for use in village health facilities, has the potential to improve delays in diagnosis.…”

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

“…The doublet was effective for treatment of second-stage experimental infections with human pathogenic T. b. rhodesiense and T. b. gambiense isolates, at a dose of deoxycoformycin similar to or lower than those used in leukaemia patients. The drug combination has been tested in clinical trials for other indications (174 …”

In Vitro and In Vivo Activities of 2-Aminopyrazines and 2-Aminopyridines in Experimental Models of Human African Trypanosomiasis

“…or oral treatment of the nucleoside analogue cordycepin (3=-deoxyadenosine) at doses of 2 mg/kg together with the adenosine deaminase inhibitor deoxycoformycin cures mice after parasites have penetrated into the brain in a late-stage infection model of human African trypanosomiasis (8). Although showing promise in the lab, until these and other candidates have proven effective in a clinical setting, there is a sustained need to continuously identify new chemotypes from which novel therapies can be developed.…”

“…In addition to the currently available therapy, several new exciting lead compounds against both stages of T. brucei subspecies infection have recently been described (6)(7)(8). Many of these are, however, not effective in animal models of late-stage disease (9,10).…”