Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors.

摘要: Abstract The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection drug-resistant strains. A new opportunity for drug intervention offered by antivirals act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) Reverse Transcriptase Ribonuclease H (RNase H) activities. Among tested compounds, dihydroxyindole-carboxamide 5 was able to inhibit in low micromolar range (1–18 μM) multiple IN, including functional IN-IN interactions, IN-LEDGF/p75 binding IN catalytic activity. Docking site-directed mutagenesis studies have suggested compound binds a previously described pocket. These observations indicate structurally mechanistically distinct from published inhibitors. Moreover, also inhibited RNase function, classifying molecule dual inhibitor impair virus replication cell culture. Overall, identified scaffold suitable platform development novel