HIV essential enzymes active site inhibitors
Since the beginning in the early 90s, we are taking advantage of the biochemical data we obtained to imagine potential novel therapeutic approaches and develop inhibitors with antiviral properties (Andreola et al, 1993). Accordingly, we have been and are still collaborating with chemists (e.g. Pr. P Cotelle, Lille; Pr. Agrofoglio, Orléans; Dr. T Burke, Frederick MD USA; Pr. R Di Santo, Roma Italy) to develop RNaseH inhibitors (Pescatori et al, 2015), IN inhibitors (Billamboz et al, 2016) or even dual inhibitors (Messore et al, 2020).
Following the approval of the first IN inhibitor for clinical use in 2007, we have studied the mechanism of action of such active site inhibitor, the molecular mechanism of resistance induced by IN mutations observed in patients (Métifiot et al, 2016), and develop original molecules with reduced susceptibility (Patent # 10,208,035). To be completed (148/143/155 etc.)
Novel therapeutic target and high throughput screening
In parallel, we are investigating novel therapeutic avenues by either rational development of molecules based on current knowledge about IN partners such as VPR (Zhao et al 2018), or high throughput screening that led to the discovery of a series of stilbene disulfonic acid derivatives interfering with IN-DNA binding (Aknin et al. 2019).
In recent years, repurposing of drugs is a hot topic as identified molecules are well documented and can access more rapidly approval for a novel application. In that direction, we know that G4-forming molecules have a propensity to inhibit HIV enzymes in vitro and we showed that anticancer molecule AS1411 is indeed antiviral (Métifiot et al, 2015) validating that this approach could be used in the case of HIV. Accordingly, we developed an AlphaScreen-based interaction assay to isolate modulators of the IN-GCN2 complex (Sidaction 2019-2021).
A proof of principle screen was performed using 133 FDA-approved drugs. We selected 5 inhibitors and 4 stimulators for further characterization and identified subsequent derivatives for preliminary SAR studies. These molecules are able to either inhibit or stimulate the IN-GCN2 interaction with pro- or antiviral properties according to their respective in vitro activities. In parallel, to explore novel therapeutic avenues, we are generating a collection of various libraries (around 3000 molecules) and actively develop in vitro assays to monitor protein-protein interactions of interest.