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In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides
C J Bacchi1, K Sanabria, A J Spiess
1Department of Biology, Pace University, New York, New York 10038, USA.
Abstract:
5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.
Insights
5'-Deoxy-5'-(hydroxyethylthio)adenosine (HETA), an analog of 5'-Deoxy-5'-(methylthio)adenosine (MTA), shows promise in treating African trypanosomiasis. HETA and its derivatives demonstrated significant curative effects against Trypanosoma brucei rhodesiense in mouse models.
Area of Science:
- Biochemistry
- Parasitology
- Medicinal Chemistry
Background:
- 5'-Deoxy-5'-(methylthio)adenosine (MTA) is a critical polyamine biosynthesis byproduct.
- MTA is cleaved by MTA phosphorylase and salvaged into adenine and methionine.
- 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), an MTA analog, is a substrate for trypanosome MTA phosphorylase.
Purpose of the Study:
- To evaluate the efficacy of HETA and its O-acylated derivatives against Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.
- To assess the potential of MTA substrate analogs as novel chemotherapies for African trypanosomiasis.
Main Methods:
- Testing HETA and three O-acylated HETA derivatives against model infections of T. b. brucei and T. b. rhodesiense in mice.
- Administering compounds via continuous infusion using osmotic pumps.
- Evaluating curative rates and lifespan extension in infected mice.
Main Results:
- HETA achieved >60% curative rates in mice infected with 5 out of 11 clinical isolates of T. b. rhodesiense.
- HETA extended the lifespan of mice infected with four additional isolates by two- to fivefold.
- Di- and tri-O-acetylated HETA derivatives were curative, while a tri-O-propionyl derivative was less effective.
Conclusions:
- HETA and its acetylated derivatives show significant potential for treating African trypanosomiasis.
- Substrate analogs of MTA warrant consideration for developing new anti-trypanosomal drugs.
- This research highlights a promising avenue for combating neglected tropical diseases.