Brinkworth R I, Fairlie D P
Centre for Drug Design and Development, University of Queensland, Brisbane, Australia.
Biochem Biophys Res Commun. 1992 Oct 30;188(2):624-30. doi: 10.1016/0006-291x(92)91102-v.
Based upon an earlier observation that sodium docosanedioate (NaO2C-(CH2)20-CO2NA) weakly inhibits HIV-1 proteinase (IC50 12 microM), we have identified a class of more potent inhibitors (sulfonic acids) of this enzyme which are likewise dianionic at pH 5-6.5. Many of the compounds were moderately strong inhibitors of the enzyme (IC50 40nM-10 microM) and some have previously been shown to have anti-HIV activity in lymphocytes. Proteinase inhibition was dependent on the separation between sulfonate/carboxylate substituents, consistent with the hypothesis that negative charged ends of an inhibitor might form ionic bonds with Arg 8 and Arg 108 located at either end of the substrate-binding groove of the enzyme. The binding mode remains to be established by structure elucidation. Results for enzyme inhibition are presented along with structure-activity relationships and evidence for pH dependent inhibition. The general observations reported here may be useful for developing more potent and selective non-peptidic proteinase inhibitors.
基于早期的一项观察，即二十二碳二酸钠（NaO2C-(CH2)20-CO2Na）对HIV-1蛋白酶有微弱抑制作用（IC50为12微摩尔），我们已鉴定出一类该酶的更有效抑制剂（磺酸类），它们在pH 5 - 6.5时同样为双阴离子。许多此类化合物是该酶的中度强效抑制剂（IC50为40纳摩尔 - 10微摩尔），并且一些之前已被证明在淋巴细胞中具有抗HIV活性。蛋白酶抑制作用取决于磺酸根/羧酸根取代基之间的间距，这与抑制剂带负电荷的末端可能与位于该酶底物结合凹槽两端的精氨酸8和精氨酸108形成离子键的假设一致。结合模式仍有待通过结构解析来确定。本文给出了酶抑制结果以及构效关系和pH依赖性抑制的证据。此处报道的一般观察结果可能有助于开发更有效和更具选择性的非肽类蛋白酶抑制剂。
