Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents
A significant medicinal strategy toward Aids cure aims to reverse latency in infected cells like a initial step resulting in their elimination. As the impartial identification of molecular targets physically connected using the latent Aids-1 provirus could be highly valuable to solve the molecular determinants of Aids-1 transcriptional repression and latency reversal, because of technical limitations, it has been challenging. Ideas make use of a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to probe the differential protein composition from the latent and activated Aids-1 5’LTR. Catchet-MS identified known and novel latent 5’LTR-connected host factors. Of these, IKZF1 is really a novel Aids-1 transcriptional repressor, needed for Polycomb Repressive Complex 2 recruitment towards the LTR.
We discover the clinically advanced thalidomide analogue iberdomide, and also the Food and drug administration approved analogues lenalidomide and pomalidomide, to become novel LRAs. We show, by targeting IKZF1 for degradation, these compounds reverse Aids-1 latency in CD4 T-cells isolated from virally covered up people coping with CC220 Aids-1 which they could synergize along with other known LRAs.