Effects of SKF 108922, an HIV-1 protease inhibitor, on retrovirus replication in mice.
Effects of SKF 108922, an HIV-1 protease inhibitor, on retrovirus replication in mice.
复制标题
SKF 108922（一种 HIV-1 蛋白酶抑制剂）对小鼠逆转录病毒复制的影响。
DOI：
10.1016/0166-3542(95)00831-4
复制
发表时间：
1996
影响因子：
7.6
通讯作者：
Lambert,D
中科院分区：
文献类型：
--
作者：
Black,Pl;Ussery,MA;Barney,S;Wittrock,R;DeMarsh,P;Dreyer,GB;PettewayJr,SR;DalMonte,P;Baldoni,J;Lambert,D
合理设计的合成逆转录病毒蛋白酶抑制剂可抑制感染 1 型人类免疫缺陷病毒 (HIV-1) 的人 T 淋巴细胞培养物中病毒多肽的加工，从而在体外抑制 HIV-1 的感染性。我们之前报道了HIV-1蛋白酶抑制剂对C型逆转录病毒Rauscher鼠白血病病毒（RMuLV）和慢病毒猴免疫缺陷病毒（SIV）的体外抗病毒活性。阻断 HIV-1 感染性的相同化合物在体外也抑制 RMuLV 和 SIV 的感染性。本报告通过在 RMuLV 模型中测试体内 HIV-1 蛋白酶抑制剂的抗病毒活性来扩展这些发现。 RMuLV 感染的小鼠通过腹膜内 (IP) 途径每天两次（bid）用活性化合物（SKF 108922）或无活性化合物（SKF 109273）治疗十四天。与赋形剂对照相比，用羟丙基-β-环糊精 (HPB) 配制的 SKF 108922 降低了病毒引起的脾肿大、病毒血症和血清逆转录酶 (RT) 水平，而 SKF 109273 则无活性。 HPB 车辆本身增强了 RMuLV 的复制。研究了改变制剂和给药途径的效果。 SKF 108922 采用 HPB 配制，通过 IP 或皮下 (SC) 途径给药时具有类似的抗病毒活性。然而，以硫酸胆固醇 (CS) 中的胶体悬浮液形式施用的 SKF 108922 没有可检测到的抗病毒作用。血浆中蛋白酶抑制剂循环水平的测量解释了这一结果。 SC 施用溶于 HPB 的化合物后 10 分钟内 SKF 108922 的血浆浓度超过 1000 nM，但 SC 施用与 CS 配制的相同剂量后，血浆中未检测到 SKF 108922。有关施用这些药物的最佳条件的信息应该有助于指导其临床应用。因此，RMuLV 应该为此类治疗 HIV 的药物的临床前评估和开发提供良好的模型。
Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polypeptides in cultures of human T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1) and therefore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) and the lentivirus simian immunodeficiency virus (SIV). The same compounds which blocked the infectivity of HIV-1 also inhibited the infectivity of RMuLV and SIV in vitro. This report extends these findings by testing the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) with either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (IP) route. Compared with excipient control, SKF 108922, formulated with hydroxypropyl-β-cyclodextrin (HPB), reduced virus-induced splenomegaly, viremia, and serum reverse transcriptase (RT) levels, while SKF 109273 was inactive. The HPB vehicle by itself enhanced replication of RMuLV. The effects of changing the formulation and the route of administration were examined. SKF 108922, formulated in HPB, had similar antiviral activity when administered by the IP or subcutaneous (SC) routes. However, SKF 108922 administered as a colloidal suspension in cholesterol sulfate (CS) had no detectable antiviral effect. Measurements of the circulating levels of the protease inhibitor in plasma explained this result. Plasma concentrations of SKF 108922 exceeded 1000 nM within 10 min after SC administration of the compound solubilized in HPB, but SKF 108922 was not detected in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, RMuLV should provide a good model for the preclinical evaluation and development of this class of agents for the treatment of HIV.