New compounds to study neurological disorders related to autophagic dysfunction

Denton, Travis

Abstract

New compounds to study neurological disorders related to autophagic dysfunction Neurological disorders are debilitating diseases that are plaguing world health. For example, as many as 15,000 people in the United States have Amyotrophic Lateral Sclerosis (ALS), more than 2.3 million people are affected by Multiple Sclerosis (MS) worldwide and, as of 2013, and as many as 5 million Americans were living with Alzheimer's disease (AD). Lanthionine ketimine (LK) is a natural amino acid metabolite found in mammalian brain tissue at low concentrations and possess potent neuroprotective, neurotrophic and anti-neuroinflammatory properties and may lead research into new medicines to treat neurological disorders such as MS, AD and ALS. It has been demonstrated that LK, and its brain permeable derivative lanthionine ketimine ethyl ester (LKE) activate the process of cellular autophagy, a natural recycling program that is compromised in diseases such as ALS, MS and AD. LKE has proven to be safe and orally bioavailable in rodents and it has been shown to remarkably reduce AD-like pathology and ALS in transgenic mouse models. LKE has been to shown to improve function in models of MS; Batten disease; Duchenne muscular dystrophy; traumatic brain injury and spinal cord hemisection, all conditions in which autophagic dysfunction has been noted. We hypothesize that, using LK and LKE as lead compounds, a new molecule capable of treating these neurological diseases can be prepared. We have recently developed novel chemical approaches that allow access to new regions of structure-activity space around the LK core structure.
In Aim 1 we will optimize the synthesis of the initial library of LK analogues, in Aim 2 we will synthesize and purify new monoalkyl phosphonates and incorporate a monoalkyl phosphonate moiety to create LK-PEs (LK-P mono esters) in an effort to increase the hydrophobic character of the compound for augmented cell permeability and, in Aim 3, we will determine the ability of the compounds prepared in Aims 1-2 to increase cellular autophagy in quantitative cell based assays. At the conclusion of these studies, we intend to have a set of compounds that will lead the way to the development of a treatment for one or more of these devastating neurological diseases.

Public Health Relevance

New compounds to study neurological disorders related to autophagic dysfunction As many as 15,000 people in the United States have Amyotrophic Lateral Sclerosis (ALS), more than 2.3 million people are affected by Multiple Sclerosis (MS) worldwide and, as of 2013, and as many as 5 million Americans were living with Alzheimer's disease (AD). New medications for the treatment of these debilitating diseases are necessary and the NIH R15 proposal submitted by Travis T. Denton of Washington State University, College of Pharmacy is aiming to just this.