SPPL3 Inhibitors

SPPL3 inhibitors encompass a variety of compounds that target the proteolytic activity of the signal peptide peptidase-like 3 (SPPL3) protein, a member of the intramembrane-cleaving proteases. These inhibitors typically function by either directly blocking the active site of SPPL3 or competing with natural substrates, thereby preventing the cleavage of type II membrane proteins. For example, LY-374973, DAPT, L-685,458, and Semagacestat are gamma-secretase inhibitors but are considered potential indirect inhibitors of SPPL3 due to the functional and mechanistic similarities between gamma-secretase and SPPL3. They impede the proteolytic processing of substrates by SPPL3, which relies on the cleavage of intramembrane sites to exert its function. By either mimicking the transition state of the substrate or competing for binding at the active site, these inhibitors can decrease the functional activity of SPPL3.

Moreover, some inhibitors like TAPI-1 and (R)-Thiorphan target the active site metal ions critical for SPPL3's protease activity. TAPI-1 acts as a broad-spectrum metalloprotease inhibitor and potentially inhibits SPPL3 by chelating the metal ions, thus rendering the enzyme inactive. Similarly, (R)-Thiorphan, a neprilysin inhibitor, can inhibit SPPL3 by depriving it of the metal ions necessary for its enzymatic function. Batimastat, another broad-spectrum inhibitor, can potentially bind to the catalytic site of SPPL3, directly impeding the processing of its substrates.