Abdurahman Samir, Végvári Akos, Youssefi Masoud, Levi Michael, Höglund Stefan, Andersson Elin, Horal Peter, Svennerholm Bo, Balzarini Jan, Vahlne Anders
Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Antimicrob Agents Chemother. 2008 Oct;52(10):3737-44. doi: 10.1128/AAC.00265-08. Epub 2008 Jul 21.
Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.
在人类免疫缺陷病毒1型（HIV-1）病毒粒子成熟过程中，病毒蛋白酶对Gag前体蛋白进行蛋白水解切割后，衣壳蛋白p24会发生形态变化，最终将病毒核心从不成熟的球形转变为成熟的锥形结构。病毒粒子的感染性严重依赖于衣壳锥形结构的最佳半稳定性。我们之前报道过，甘氨酰胺（G-NH(2)）添加到受感染细胞的培养基中时，会抑制HIV-1复制，并且会形成具有异常核心结构的HIV-1颗粒。在此我们表明，具有抗病毒活性的不是G-NH(2)本身，而是其代谢产物α-羟基甘氨酰胺（α-HGA）。我们发现，α-HGA可抑制对逆转录酶和蛋白酶抑制剂产生获得性耐药的临床HIV-1分离株的复制，但对10种不同的RNA和DNA病毒中的任何一种的复制均无影响。α-HGA可能通过与HIV-1衣壳蛋白N端和C端结构域之间的铰链区结合，从而在体外和体内影响HIV-1衣壳蛋白组装成管状或核心结构的能力，基质辅助激光解吸电离质谱结果表明了这一点。作为一种抗病毒化合物，α-HGA具有异常简单的结构、显著的抗病毒特异性和新颖的抗病毒作用机制。因此，它可能被证明是一类新型抗HIV物质的先导化合物。
