In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides

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.

Mapping the metabolism of five amino acids in bloodstream form Trypanosoma brucei using U-13C-labelled substrates and LC–MS

“…However, Creek et al showed this is not the case. Labelling with 50% U- 13 C l -methionine and identifying its metabolic products both within the parasites and their medium has given more insight into the fate of MTA, whose accumulation is generally toxic [43,44].…”

Polyamine Metabolism as Chemotherapeutic Target in Protozoan Parasites

“…In vitro, 5' substituted MTA analogs were 500-fold more active against T. b. brucei than mammalian cells [65,66], while in vivo, HETA, the most active of the MTA analogs, cured laboratory model infections of T. b. brucei and T. b. rhodesiense isolates [66]. HETA is most likely metabolized through the pathway to yield an α-ketoacid derivative of ketomethylthiobutyrate, the penultimate intermediate in the pathway [12].…”

Extremely rapid turnover of S‐adenosylmethionine decarboxylase in Crithidia fasciculata

“…Although results from inhibitor studies [14,15] as well as gene targeting [13] have demonstrated that AdoMetDC ful¢lls important functions in trypanosomal growth, there are surprisingly few studies on the activity of this enzyme during growth of the parasites. Seltzer et al [19] demonstrated a close relationship between AdoMetDC activity and cell growth of T. brucei.…”

“…Furthermore, a variety of inhibitors against AdoMetDC have been shown to exert strong anti-parasitic e¡ects [2]. Two of the most potent drugs against murine T. brucei infections were shown to be the AdoMetDC inhibitors, MDL 73811 [14] and CGP40251A [15], which, in contrast to DFMO, also cured mice infected with T. brucei rhodesiense, the causative agent of the East African form of sleeping sickness. Interestingly, the anti-protozoan drugs berenil and pentamine were both demonstrated to be e¡ective inhibitors of trypanosomal AdoMetDC [16].…”

“…Adenosyl-L-[carboxy-14 C]methionine (58 mCi/mmol) and AdoMet were purchased from Amersham (Amersham, UK) and Sigma (St. Louis, MO, USA), respectively. SuperSignal West Dura and horseradish peroxidase conjugated goat ant-rabbit IgG were bought from Pierce (Rockford, IL, USA).…”