Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity

Abstract

Drug repurposing offers a validated approach to reduce drug attrition within the drug discovery and development pipeline through the application of known drugs and drug candidates to treat new indications. Full exploitation of this strategy necessitates the screening of a vast number of molecules against an extensive number of diseases of high burden or unmet need and the subsequent dissemination of the findings. In order to contribute to endeavours within this field, we screened the 727 compounds comprising the US National Institutes of Health (NIH) Clinical Collection through an HIV-1 (human immunodeficiency virus type 1) integrase stand transfer inhibition assay on an automated scintillation proximity assay platform. Only two compounds were identified within the initial screen, with cefixime trihydrate and epigallocatechin gallate found to reduce integrase strand transfer activity at IC50 values of 6.03±1.29 μM and 9.57±1.62 μM, respectively. However, both cefixime trihydrate and epigallocatechin gallate retained their low micromolar inhibitory activity when tested against a raltegravir-resistant integrase double mutant (FCIC50 values of 0.83 and 0.06, respectively), were ineffective in an orthogonal strand transfer ELISA (less than 30% inhibition at 100 μM) and produced negligible selectivity index values (less than 1) in vitro. While no useful inhibitors of HIV-1 integrase strand transfer activity were found within the NIH Clinical Collection, the identification of two assay-disrupting molecules demonstrates the importance of consideration of non-specific inhibitors in drug repurposing screens.

Identifying Small Molecules That Promote Quasipalindrome-Associated Template-Switch Mutations inEscherichia coli

“…The NIH Clinical Collection, a library containing 700 small molecules ( Supplementary Table 1), was utilized in the screen. This library has been used previously to discover anti-coronavirus drugs (Cao et al 2015) and inhibitors of HIV-1 integrase activity (Abrahams et al 2018). The screen was conducted using two different concentrations: 10 mM and 80 mM.…”

Quinoline Functionalized Schiff Base Silver (I) Complexes: Interactions with Biomolecules and In Vitro Cytotoxicity, Antioxidant and Antimicrobial Activities

“…The cytotoxicity assay was conducted as per the standard method and as described by Abrahams et al 2018 [ 111 ]. Briefly, 96-well microtiter plates were seeded with HEK293 (non -cancerous cell line), HELA, MDA-MB231, and SHSY5Y at a concentration of 1 × 10 5 cells/mL and allowed to stabilize for 4 h at 37 °C and 5% CO 2 .…”

Mononuclear discrete Ag(I) complexes of aryl substituted (E)-N-phenyl-1-(pyridin-3-yl)methanimine: In vitro biological activities and interactions with biomolecules

“…Complexes 3a, 3b and 3c were selected for cytotoxicity based on our previous study 38 , where remarkable anticancer activity and high selectivity of Ag(I) complexes bearing the CH 3 substituent were identified. The cytotoxicity experiment was performed using Abrahams et al 2018 39 methods, in which 1 × 10 5 cells per mL of HEK293 (non-cancerous cell line), HELA, MDA-MB231 and A375 were seeded in 96-well microtiter plates and allowed to stabilize for 4 hours at 37 °C and 5% CO 2 . Then, through two-fold serial dilution, 3a, 3b, 3c and Cisplatin were added to the plate, resulting in eight final compound concentrations ranging from 100 to 0.781 µM in a total volume of 200 µL per well.…”