Researchers from the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute say they have identified a compound that is a promising candidate for inhibiting the production of amyloids inside the brains of patients with Alzheimer’s disease. They described the compound (known as C1) in an accepted online manuscript (“Substrate Interaction Inhibits γ-secretase Production of Amyloid-β Peptides”) in the Royal Society of Chemistry’s Chemical Communications. C1 uses a novel mechanism to prevent the enzyme gamma-secretase from producing amyloids, according to the scientists.
C1 is a covalent gamma-secretase inhibitor that blocks the active site on the precursor protein where gamma-secretase would bind to transform it into amyloids, rather than blocking the active site on gamma-secretase itself as traditional enzyme inhibitors do.
“Historically, drug trials for gamma-secretase inhibitors failed because traditional enzyme inhibitors have severe side effects. They stopped all of the normal functions of gamma-secretase,” said Chunyu Wang, PhD, a professor of biological sciences. “Our compound binds to the cleavage site of the precursor protein instead of the enzyme itself, which may avoid many problems associated with traditional enzyme inhibitors.”
In 2018, with support from the Warren Alpert Foundation, Wang began screening drugs to identify a compound that targets the amyloid precursor protein substrate, which would block the activity of gamma-secretase involved in amyloid production while allowing all other functions. He began the search with in silico screening, using computer modeling to test tens of millions of compounds.
C1 was one of several candidates to emerge from that screening. As described in the paper, C1 blocks amyloid production with high efficiency when present at micromolar concentrations, both in test tubes and in cell culture, noted Wang. The research is patent pending.
C1 is a covalent inhibitor. Wang said that because of their permanent bond, covalent inhibitors are more durable than their noncovalent counterparts. Covalent inhibitors make up about one-third of the drug market, even though they have traditionally been viewed as having a higher risk of causing immune reactivity. In recent years, there has been a surge in the development of covalent inhibitors, as more highly specific covalent inhibitors showed excellent efficacy towards challenging drug targets, explained Wang.