Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy.
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy.
Eur J Med Chem. 2014 May 6;78:425-30. doi: 10.1016/j.ejmech.2014.03.070. Epub 2014 Mar 25.
HIV-1 Integrase (IN) represents a very attractive pharmacological target for the development of new and more efficient drugs. Recently, an allosteric inhibitory approach also emerged, that targets the interaction between IN and cellular cofactors, such as LEDGF/p75. Small molecules based on the diketoacid pharmachophore were studied for their ability to inhibit at the same time integration and IN-LEDGF/p75 interaction (dual inhibitors): in this study, we evaluated three indole diketoacid derivatives and their magnesium(II) complexes for their ability to act as dual inhibitors. Effectively, the metal complexes exhibited IN inhibition potency in low nanomolar/micromolar concentration range; both the complexes and the free ligands are also able to inhibit the IN-LEDGF/p75 interaction at low μM values. Moreover, these magnesium compounds showed good antiviral activity, suggesting the possibility to exploit metal coordination for the design of new antivirals.
HIV-1 整合酶（IN）是开发新型、更有效的药物的极具吸引力的药理学靶标。最近，一种变构抑制方法也出现了，该方法针对 IN 与细胞辅助因子（如 LEDGF/p75）之间的相互作用。基于二酮酸药效团的小分子因其同时抑制整合和 IN-LEDGF/p75 相互作用（双重抑制剂）的能力而被研究：在这项研究中，我们评估了三种吲哚二酮酸衍生物及其镁（II）配合物作为双重抑制剂的能力。实际上，金属配合物以低纳摩尔/微摩尔浓度范围表现出 IN 抑制效力；配合物和游离配体均能够以低 μM 值抑制 IN-LEDGF/p75 相互作用。此外，这些镁化合物表现出良好的抗病毒活性，表明可以利用金属配位来设计新型抗病毒药物。
