Bacchi C J, Sanabria K, Spiess A J, Vargas M, Marasco C J, Jimenez L M, Goldberg B, Sufrin J R
Department of Biology, Pace University, New York, New York 10038, USA.
Antimicrob Agents Chemother. 1997 Oct;41(10):2108-12. doi: 10.1128/AAC.41.10.2108.
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.
5'-脱氧-5'-(甲硫基)腺苷（MTA）是多胺生物合成的关键副产物，可被MTA磷酸化酶裂解，并作为腺嘌呤被挽救，通过核糖部分的转化生成甲硫氨酸。MTA的类似物5'-脱氧-5'-(羟乙基硫基)腺苷（HETA）是锥虫MTA磷酸化酶的底物，在体外和体内对布氏锥虫（牛锥虫病的病原体）均有活性。在本研究中，检测了HETA及其三种O-酰化HETA衍生物对布氏锥虫和东非昏睡病病原体罗德西亚锥虫模型感染的活性。当以200mg/kg体重通过渗透泵连续输注7天给予小鼠时，HETA对11株罗德西亚锥虫临床分离株中的5株引起的感染具有治愈作用（>60%）。150至200mg/kg的HETA还使感染另外四种分离株的小鼠寿命延长了2至5倍。HETA的二-O-乙酰化和三-O-乙酰化衍生物也被证明对感染具有治愈作用，而三-O-丙酰化衍生物虽然也有治愈作用，但效果不如前者。本研究表明，MTA的底物类似物应作为抗非洲锥虫病的新型化疗药物开发的重要考虑对象。
