CGP-53437, AN ORALLY BIOAVAILABLE INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE WITH POTENT ANTIVIRAL ACTIVITY
CGP-53437, AN ORALLY BIOAVAILABLE INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE WITH POTENT ANTIVIRAL ACTIVITY
复制标题
DOI：
10.1128/aac.37.10.2087
复制
发表时间：
1993-10-01
影响因子：
4.9
通讯作者：
WOODSCOOK, K
中科院分区：
文献类型：
--
作者：
ALTERI, E;BOLD, G;WOODSCOOK, K
CGP 53437是一种含有羟乙基同工酶的人类免疫缺陷病毒1型蛋白水解酶的模拟多肽抑制剂。该化合物抑制重组HIV-1蛋白水解酶，其K(I)为0.2 nM。对人组织蛋白酶D和人组织蛋白酶E的抑制常数为4 nM。K(I)S分别抑制人胃酶和胃蛋白酶，K(I)分别为8和500nM，K(I)为190um。在急性感染的MT-2细胞中，HIV-1/LAV、HIV-1/Z-84和HIV-1/PLAI的复制被抑制，有效剂量为0.1um的90%。50%细胞毒剂量为100微米。在感染后10h加入该化合物后，观察到类似的抗病毒活性。在有效浓度下，Gag前体蛋白P55的加工大大减少，证实了对病毒生命周期后期的作用，正如预期的那样。用感染HIV-1/LAV株的原代人外周血淋巴细胞、从HIV-1血清阳性个体获得的低传代临床分离株(包括齐多夫定耐药株)和HIV-2/Rod也证明了该抑制剂的有效性。在这些细胞中，只要抑制物保持在培养中，cgp 53437就以剂量依赖的方式延迟艾滋病毒复制的开始(浓度大于或等于0.1um的显著影响)。CGP-53437在小鼠体内具有口服生物利用度。口服120 mg/kg后，血浆浓度可持续数小时，超过体外抗病毒90%有效剂量10倍。因此，CgP-53437有可能成为治疗艾滋病的有效抗HIV药物。
CGP 53437 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease containing a hydroxyethylene isostere. The compound inhibited recombinant HIV-1 protease with a K(i) of 0.2 nM. The inhibition constant versus human cathepsin D and human cathepsin E was 4 nM. Human pepsin and gastricsin were inhibited with K(i)s of 8 and 500 nM, respectively, and human renin was inhibited with a K(i) of 190 muM. The replication of HIV-1/LAV, HIV-1/Z-84, and HIV-1/pLAI was inhibited with a 90% effective dose of 0.1 muM in acutely infected MT-2 cells. The 50% cytotoxic dose was 100 muM. Similar antiviral activity was observed when the compound was added up to 10 h after infection. At the effective concentration, processing of Gag precursor protein p55 was greatly reduced, confirming an action on the late stage of the virus life cycle, as expected. The efficacy of the inhibitor was also demonstrated by using primary human peripheral blood lymphocytes infected with the HIV-1/LAV strain, low-passage clinical isolates obtained from HIV-1-seropositive individuals (including a zidovudine-resistant strain), and HIV-2/ROD. In these cells, CGP 53437 delayed the onset of HIV replication in a dose-dependent fashion (substantial effects with concentrations of greater-than-or-equal-to 0.1 muM) as long as the inhibitor was maintained in the culture. CGP 53437 was orally bioavailable in mice. Concentrations in plasma 10-fold in excess of the in vitro antiviral 90% effective dose could be sustained for several hours after oral application of 120 mg/kg. Therefore, CGP 53437 has the potential to be a therapeutically useful anti-HIV agent for the treatment of AIDS.