A NOVEL CLASS OF RETINOID ANTAGONISTS AND THEIR MECHANISM OF ACTION

Retinoids regulate a broad range of biological processes through two s ubfamilies of nuclear retinoid receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently, we reported a no vel type of retinoic acid antagonist (SR11335) and showed that this co mpound can inhibit retinoic acid (RA) induced activation of a human im munodeficiency virus type 1 (HIV-l) promoter construct that contains a special RA response element (RARE). We have now further characterized the antagonism mediated by SR11335 and of newly synthesized structura lly related compounds, Two compounds, SR11330 and SR11334, which are p oor transactivators, also showed antagonist activities, inhibiting all -trans RA (tRA) and g-cis-RA. The retinoids inhibited transcriptional activation of RAR/RXR heterodimers effectively, while inhibition of RX R homodimers was less efficient. Inhibition was observed on several RA REs, including the TREpal, beta RARE, apoAI-RARE, and CRBPI-RARE, In a ddition, the antag.nists inhibited tRA-induced differentiation of HL-6 0 cells, The antagonist did not interfere with DNA binding of the rece ptors. In limited proteolytic digestion assays, SR11335 induced resist ance of the receptors to proteolysis, but the pattern of the degradati on was not altered from that induced by tRA, suggesting that these ant agonists induce their biological effects by competing with agonists fo r binding to RARs, thereby preventing the induction of conformational changes of the receptors necessary for transcriptional activation.