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评估核苷膦酸酯及其类似物和前药对正痘病毒复制的抑制作用。

Evaluation of nucleoside phosphonates and their analogs and prodrugs for inhibition of orthopoxvirus replication.

作者信息

Keith Kathy A, Hitchcock Michael J M, Lee William A, Holý Antonin, Kern Earl R

机构信息

University of Alabama School of Medicine, Birmingham, Alabama 35233, USA.

出版信息

Antimicrob Agents Chemother. 2003 Jul;47(7):2193-8. doi: 10.1128/AAC.47.7.2193-2198.2003.

Abstract

In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl L-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC(50)s) from 4 to 8 microM, compared with 33 to 43 microM for CDV. Although PMEA itself was not active, adefovir dipivoxil [bis[(pivaloyl)oxymethyl] PMEA] and bis(butyl L-alaninyl) PMEA were active against both viruses, and bis(butyl L-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl L-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC(50)s of 0.1 to 2.6 microM. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.

摘要

万一发生使用天花病毒的生物恐怖袭击,目前尚无批准用于治疗该病毒感染的药物。我们之前曾报道,(S)-1-[3-羟基-2-(膦酰甲氧基)丙基]胞嘧啶(HPMPC)(也称为西多福韦[CDV])对痘病毒感染具有良好活性;然而,一个主要限制是需要静脉给药。两种相关的无环核苷膦酸盐(ANP),阿德福韦(PMEA)和替诺福韦(PMPA),对人类免疫缺陷病毒或乙型肝炎病毒有活性,但对正痘病毒无活性。因此,我们评估了这三种化合物的许多类似物和潜在的口服前药在组织培养细胞中抑制痘苗病毒或牛痘病毒复制的能力。CDV系列中活性最高的化合物是(S)-HPMPA和(丁基L-丙氨酰基)环HPMPC,50%有效浓度(EC50)为4至8 microM,而CDV为33至43 microM。虽然PMEA本身无活性,但阿德福韦酯[双[(新戊酰基)氧甲基]PMEA]和双(丁基L-丙氨酰基)PMEA对两种病毒均有活性,双(丁基L-丙氨酰基)PME-N6-(环丙基)DAP和(异丙基L-丙氨酰基)苯基PME-N6-(环丙基)DAP是测试的活性最高的化合物,EC50为0.1至2.6 microM。在PMPA系列中,测试的类似物均未表现出比PMPA本身显著更好的活性。这些数据表明,这些ANP衍生物中的许多在体外对痘苗病毒和牛痘病毒具有活性,应评估它们在动物模型中的疗效。

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