Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor

Abstract

Keywords:HIV-1 integrase LEDGF/p75 Protein-protein interactions Molecular docking GRID a b s t r a c tThe search of small molecules as protein-protein interaction inhibitors represents a new attractive strategy to develop anti-HIV-1 agents. We previously reported a computational study that led to the discovery of new inhibitors of the interaction between enzyme HIV-1 integrase (IN) and the nuclear protein lens epithelium growth factor LEDGF/p75. 1 Herein, we describe new findings about the binding site of LEDGF/p75 on IN employing a different computational approach. In this way further structural requirements, helpful to disrupt LEDGF/p75-IN binding, have been identified. The main result of this work was the exploration of a relevant hydrophobic region. So we planned the introduction of suitable and simple chemical modifications on our previously reported 'hit' and the new synthesized compounds were subjected to biological tests.The results obtained demonstrate that the hydrophobic pocket could play a key role in improving inhibitory efficacy thus opening new suggestions to design active ligands.

Synthesis and biological evaluation of novel antiviral agents as protein–protein interaction inhibitors

“…Spectral data are in accordance with the literature 26 . Adopting the synthetic procedure previously reported by us 14,15,19,26,27 , a mixture of suitable 3-acetyl-1-benzyl-1H-indole (3a, 4-5a,b) (1 mmol), diethyl oxalate (219 mg, 1.5 mmol) and a catalytic amount of NaOCH 3 was suspended in anhydrous THF (2 mL). The reaction mixture was placed in a cylindrical quartz …”

“…Using the synthetic procedure previously reported by us 14,15,[25][26][27] , 3-acetyl-4-methoxy-1H-indole (2a) (189 mg, 1 mmol) or 3-acetyl-4-hydroxy-1H-indole (2b) (159 mg, 0.001 mol) was dissolved in DMF (1 mL) at 0 C and dry sodium hydride (120 mg, 5 mmol) or K 2 CO 3 (138 mg, 1 mmol) was added. After stirring for 2 min, the suitable benzyl bromide (1.5 mmol) was added dropwise.…”

“…Synthesis of 3-acetyl-4-methoxy-1H-indole (2a) and 3-acetyl-4-hydroxy-1H-indole (2b) was carried out following the previously reported procedure 14,15,25 . Phosphoryl chloride (0.92 mL, 10 mmol) was added to ice cold dimethylacetamide (2.79 mL, 30 mmol) under stirring and cooling in ice.…”

“…In previous research from our laboratory, it was found that N-benzyl-indoles, bearing diketo acid moiety, were able to exert a specific blockade of the IN/LEDGF interaction [14][15][16][17][18] and among them we found CHI-1043, CHIBA-3000 and some methylbenzyl derivatives such as CHIBA-3017 and CHIBA-3053 ( Figure 1) as interesting PPI inhibitors 14,19 . Encouraged by these promising results, which could represent an interesting starting point for the development of novel dual drugs, and with the aim of achieving further information about the IN/LEDGF protein interaction, we focused our efforts to synthesize new indole analogues.…”

A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain

“…The emergence of fragment-based drug discovery, which entails screening of libraries of small molecule compounds (typically Ͻ250 Da) using either biophysical techniques or enzymatic assays, has opened a novel avenue for the identification of new inhibitors that bind at the IN-LEDGF/p75 interface (31). Several new chemical classes of IN-LEDGF/p75 inhibitors, including benzylindoles (32,33), benzodioxole-4-carboxylic acid (34), and 8-hydroxyquinoline (35), have been identified using in silico methods coupled with fragment-based approaches using surface plasmon resonance or nuclear magnetic resonance (NMR) spectroscopy as primary screening methods. However, further development of these initial fragment hits was hindered by the lack of structural data.…”