A newly identified compound is a promising candidate for inhibiting
the production of amyloids, the abnormal proteins that form toxic
clumps, called fibrils, inside the brains of patients with Alzheimer’s
disease. As published today in the Royal Society of Chemistry’s
Chemical Communications, the compound—known as “C1″—uses a novel mechanism to efficiently prevent the enzyme gamma-secretase from producing amyloids.
Amyloid fibrils are largely composed of the peptide Amyloid beta,
which is produced when enzymes, including gamma secretase, make cuts to
the
amyloid precursor protein
found in high concentrations the membrane of brain cells. 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—as traditional enzyme inhibitors do—blocking the
active site on gamma-secretase itself.
“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, a professor of
biological sciences and member of the Center for Biotechnology and
Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute.
“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. The research is patent pending.
C1 is a covalent inhibitor, meaning it forms a chemical bond with its
target. Wang said that because of their permanent bond, covalent
inhibitors are more durable than their non-covalent 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 is surge in the
development of covalent inhibitors, as more highly specific covalent
inhibitors showed excellent efficacy towards challenging drug targets.
“With a new approach to tackling the principal pathology of
Alzheimer’s disease, Chunyu’s work is generating a fresh roster of drug
candidates with enormous promise,” said Deepak Vashishth, the director
of CBIS. “His works speaks to the power of the interdisciplinary culture
of research at CBIS, and we are pleased with this early result.”
More information: “Substrate Interaction Inhibits gamma-secretase Production of Amyloid-B peptides,” Chemical Communications (2020).
