Senior Vice President of Platform Atavistik Bio Cambridge, Massachusetts
Endogenous cellular metabolites allosterically regulate a myriad of biological functions through interactions at the molecular level. Often, metabolites are used as biomarkers in disease, including the most widely known examples of glucose in diabetes or cholesterol in cardiovascular disease. In addition to being biomarkers and catalytic substrates for proteins, they also serve to regulate proteins through direct and indirect interaction, including a myriad of processes, from signaling and transcriptional networks to cytoskeletal assemblies.
Until recently, there have been no methods to discover functional metabolite regulatory sites in proteins on a large scale. Atavistik Bio has developed the AMPS (Atavistik Metabolite Protein Screening) platform, based on the work of the Rutter lab at University of Utah, to systematically screen metabolites against proteins of interest to identify novel metabolite binding sites. The AMPS platform technology integrates equilibrium dialysis with sensitive mass-spectrometry to screen an optimized metabolite library. The binders identified by this technique are evaluated for functionality and the metabolite/protein structures are determined using crystallography or other structural biology techniques. Utilizing advanced informatics tools, deep expertise in chemistry, and computationally-rich structure-based drug design, we use the resulting information to identify novel regulatory mechanisms and exploit these interactions in important disease-relevant pathways to drive the discovery of novel therapeutics.
As an example of the utility of metabolomics throughout the entire drug discovery process, the target of an IEM will be presented from the screen, where novel functional binders were discovered, through the early drug discovery process. Follow up analysis validates the AMPS hits as bona-fide binders capable of enzyme stabilization. An enzyme stabilizer was further characterized and was found to stabilize not only the wild-type enzyme but also a mutant form of the enzyme that causes a monogenic inborn error of metabolism. Analogs of top metabolite hits were further screened, and more potent metabolite analogs were identified with biochemical and cell-based activity. In addition to the screen, a biomarker strategy that uses metabolomics as an analysis technique will be presented. Mass spec based biomarkers that are currently evaluated in patients that have the disease are also used as markers in the in vitro and cell-based assays for rapid and efficient translation from the discovery phase through the clinical setting. This example demonstrates the potential of metabolomics to empower efficient drug discovery throughout the entire the drug discovery process.
Learning Objectives:
Discuss the utility of metabolomics as a tool for drug discovery and for efficient biomarker development.
Identify ways that metabolomics can help to identify and translate PD and efficacy biomarkers for new programs.
Utilize metabolites as baits to dicovery and develop novel allosteric regulatory sites.