Sunkara P S, Kang M S, Bowlin T L, Liu P S, Tyms A S, Sjoerdsma A
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Ann N Y Acad Sci. 1990;616:90-6. doi: 10.1111/j.1749-6632.1990.tb17831.x.
Inhibitors of glycoprotein processing enzymes have been shown to have activity against HIV. Several analogues of the known glucosidase I inhibitor, castanospermine (CAST), were synthesized and evaluated for their inhibitory effect on glucosidases and for antiviral activity against Moloney murine leukemia virus (MOLV) and HIV-1. The most effective analogue was 6-O-butanoyl CAST (B-CAST, MDL 28,574) with an IC50 of 0.05 micrograms/mL against MOLV. A correlation between inhibition of glucosidase I and MOLV replication was observed. This analogue was further evaluated against HIV-induced syncytial formation in HeLa T4+ cells and against productive infection in JM cells infected with HIV 1 (GB8 strain). B-CAST showed an IC50 of 0.3 micrograms/mL in the HeLa T4+ assay, compared to CAST at 11 micrograms/mL. The compound also was more potent (IC50:0.15 micrograms/mL) than CAST (4-6 micrograms/mL) in JM cells. The antiretroviral activity of B-CAST was further confirmed in Friend leukemia virus (FLV) infection in mice. B-CAST showed equivalent activity to AZT and was more potent than CAST in inhibiting FLV-induced splenomegaly in mice. The data presented herein suggest the potential of these novel glucosidase inhibitors as anti-HIV agents.
糖蛋白加工酶抑制剂已被证明对艾滋病毒有活性。合成了已知的葡糖苷酶I抑制剂栗精胺（CAST）的几种类似物，并评估了它们对葡糖苷酶的抑制作用以及对莫洛尼氏鼠白血病病毒（MOLV）和HIV-1的抗病毒活性。最有效的类似物是6-O-丁酰基CAST（B-CAST，MDL 28,574），对MOLV的IC50为0.05微克/毫升。观察到葡糖苷酶I的抑制与MOLV复制之间存在相关性。进一步评估了该类似物对HeLa T4+细胞中HIV诱导的合胞体形成以及对感染HIV 1（GB8株）的JM细胞中生产性感染的作用。在HeLa T4+试验中，B-CAST的IC50为0.3微克/毫升，而CAST为11微克/毫升。在JM细胞中，该化合物也比CAST（4-6微克/毫升）更有效（IC50：0.15微克/毫升）。B-CAST在小鼠Friend白血病病毒（FLV）感染中的抗逆转录病毒活性得到进一步证实。B-CAST显示出与齐多夫定相当的活性，并且在抑制小鼠FLV诱导的脾肿大方面比CAST更有效。本文提供的数据表明这些新型葡糖苷酶抑制剂作为抗HIV药物的潜力。
