Sumner-Smith M, Zheng Y, Zhang Y P, Twist E M, Climie S C
Allelix Biopharmaceuticals Inc., Mississauga, Ontario, Canada.
Drugs Exp Clin Res. 1995;21(1):1-6.
N-alpha-acetyl-nona-D-arginine amide acetate (ALX40-4C) was developed as a competitive inhibitor of the binding of the HIV Tat protein to its RNA target TAR, which is an intracellular interaction dependent on a short, arginine-rich sequence in Tat. ALX40-4C is a simple mimic of that domain, which is stabilised against enzymatic degradation through inclusion of D-amino acids and terminal protection. The drug inhibits HIV-1 in vitro and is currently being assessed in vivo. In the work reported here, potential activities of the compound against other viruses were examined. As expected, there was little or no activity against most viruses examined, except against some herpesviruses: HSV-1, HSV-2 and CMV. Maximal inhibition of HSV-1 in a plaque reduction assay required pre-incubation with the drug. Maximal inhibition of HCMV, which replicates more slowly than HSV-1, requires exposure to the compound within the first few hours of infection. It appears that the drug inhibits an early step in HSV and HCMV infection. Such a mechanism is consistent with that of other cationic, herpesvirus inhibitors.
N-α-乙酰基-九-D-精氨酸酰胺乙酸盐（ALX40-4C）被开发为HIV反式激活因子（Tat）蛋白与其RNA靶标反式激活应答元件（TAR）结合的竞争性抑制剂，这是一种依赖于Tat中富含精氨酸的短序列的细胞内相互作用。ALX40-4C是该结构域的简单模拟物，通过包含D-氨基酸和末端保护来稳定其结构以抵抗酶促降解。该药物在体外抑制HIV-1，目前正在进行体内评估。在此报道的工作中，研究了该化合物对其他病毒的潜在活性。正如预期的那样，除了对一些疱疹病毒（单纯疱疹病毒1型、单纯疱疹病毒2型和巨细胞病毒）外，对大多数检测的病毒几乎没有或没有活性。在蚀斑减少试验中，对单纯疱疹病毒1型的最大抑制需要与药物预孵育。对复制比单纯疱疹病毒1型更慢的人巨细胞病毒的最大抑制需要在感染的最初几个小时内接触该化合物。看来该药物抑制单纯疱疹病毒和人巨细胞病毒感染的早期步骤。这种机制与其他阳离子疱疹病毒抑制剂的机制一致。
