Small molecule therapeutics for Alzheimer's Disease

SMALL MOLECULE THERAPEUTICS FOR ALZHEIMERandapos S DISEASE SUMMARY Alzheimerandapos s disease AD is a progressive and fatal neurological disorder that affects approximately one tenth of the population over the age of There is currently no cure for the disease The pathological hallmarks of the disease include the formation and accumulation in the brain of amyloid A Earlier therapeutic attempts at lowering total A by directly targeting the catalytic activities of or secretase were unsuccessful as the enzymes hydrolyze other substrates besides APP many with critical cellular functions Cenna has a novel technology that does not target the secretases which has yielded two potential peptide drug candidates P and P from the amino terminal domain of Presenilin PS with the ability to inhibit the production of A in vitro and in a transgenic Tg mouse model of AD We recently provided evidence that peptides P and P give a strong specific and biologically relevant binding with the purified ectodomain of APP We further demonstrated that the reduction of A by the peptides does not affect the catalytic activities of or secretase or the level of APP These peptides and their derivatives offer new potential drug candidates for the treatment of AD While P is being further developed as a peptide drug P is too unstable It is important to develop alternate back up candidates besides P It would be advantageous to identify small molecule compounds that bind APP at the same sites as P and P and by so doing also reduce A We have carried out molecular modeling studies to determine binding sites on the APP ectodomain for both P and P Having accomplished that we virtually screened a library of e compounds to identify those molecules that would be predicted to bind the same sites on APP as P and P Of the structures screened a total of suggested binding to APP at either the P or P binding site These compound have been scored and grouped In the current grant application our specific aims are To experimentally confirm by microarray analysis the binding to the APP ectodomain of the small molecule compounds identified by virtual screening To test the small molecule compounds that give positive hits for their ability to reduce A production in vitro and To test in vivo in APP Tg mice selected compounds identified in vitro to reduce A by similar amounts as P and P A successful completion of the project will provide us with small molecule candidates with the ability to reduce A in vitro and in vivo by the same mechanism as our peptide candidates As with the peptides the small molecule compounds would not be expected to affect the catalytic activities of the secretases Furthermore these compounds may be developed as oral drugs that can cross the blood brain barrier Narrative Alzheimerandapos s disease AD is a devastating degenerative neurological disorder that affects one tenth of the population over the age of There is no cure for the disease Our recent work has identified a novel approach to reduce A in vitro and in vivo with small peptides that bind the amyloid precursor protein We have used computer assisted programs to predict where these peptides bind on APP and have identified small molecule compounds with the ability to bind the same sites Our goal for the current application is to further screen these small molecule compounds in vitro and in vivo for their ability to reduce the toxic species A The successful accomplishment of this project could potentially result in small molecule disease modifying drug candidates that function like the peptides for the treatment of Alzheimerandapos s Disease