Crystallography-based fragment screening to develop pharmacological chaperones for classic HCU Principal Investigator: Thomas McCorvie, PhD
June 25, 2022
HCU Network America has announced the third recipient of the CBS deficiency global grants program – awarding a research grant to the Newcastle University Biosciences Institute in Newcastle, United Kingdom to explore a potential avenue for treatment for homocystinuria due to cystathionine beta-synthase (CBS) deficiency. The research, led by Dr. Thomas McCorvie, aims to identify stabilizers or activators of the defective enzyme in CBS-deficient homocystinuria (HCU). Dr. McCorvie is a Senior Research Associate at the Newcastle University Biosciences Institute
“Inherited mutations of Cystathionine Beta-Synthase (CBS) enzyme result in reducing its activity by destabilization and aggregation. There is precedent that small molecules which specifically bind to and stabilize CBS could restore mutant CBS activity by acting as a pharmacological chaperone (PC). Therefore, this project aims to screen for small molecules that bind to and stabilize CBS using fragment-based x-ray crystallography screening (XChem). XChem involves crystallizing the CBS protein hundreds to thousands of times and then soaking each crystal with a large library of fragments. Any small fragments that bind to CBS will be identified using x-ray crystallography and used as starting points to develop into larger molecules.”, said Dr. McCorvie.
“These potential binders will then be triaged against CBS and its disease mutants to determine if they act as PC molecules rescuing their functionality. The most promising small molecules can then be possible starting points for further preclinical studies in cell lines and animal models, and if successful can be developed as a PC therapy for classical homocystinuria.
I am incredibly honoured and excited that our proposal has been funded by the HCU Network America, as this builds on our previous work on the structural biology of CBS along with our goals to develop novel therapies for rare metabolic disorders. As such this research will leverage our group’s multi-disciplinary experience in biophysics, biochemistry, and structural-based drug screening along with guidance from our clinical contacts in the homocystinuria field.”
“We are pleased to support this research project to build upon the previous work on the crystal structure of the CBS enzyme by Drs. McCorvie and Yue, and we are hopeful that potential chaperone therapies can result from their work and be further developed into new treatments to support our patient community.” said Margie McGlynn, President of HCU Network America.
About Thomas McCorvie, PhD
McCorvie earned his BSc in biochemistry at Queen's University Belfast 2008, after where he was awarded a PhD in 2012 based on his work on the biochemical basis of galactosemia with Prof. David Timson. In 2012 he began a postdoctoral position in Prof Wyatt Yue's lab at the University of Oxford. During that time, he developed skills in x-ray crystallography of metabolic proteins involved in rare diseases with a focus on cystathionine beta-synthase (CBS). In 2016 he accepted a postdoctoral position in Prof Xiaodong Zhang's lab at Imperial College London where he further developed structural biology skills using cryo-electron microscopy (cryo-EM) towards the aim of solving structures of large protein complexes involved in DNA repair. In 2019 he returned to the lab of Prof Wyatt Yue and in 2021 was promoted to senior research associate at Newcastle University where he uses his experience to determine structures of enzyme complexes involved in carbohydrate and amino acid metabolism.
Inherited mutations of CBS result in reducing its activity by destabilization and aggregation. There is precedent that small molecules which specifically bind to and stabilize CBS could restore mutant CBS activity by acting as a pharmacological chaperone (PC). Therefore, this project aims to screen for small molecules that bind to and stabilize CBS using fragment-based x-ray crystallography screening (XChem). XChem involves crystallizing the CBS protein hundreds to thousands of times and then soaking each crystal with a large library of fragments. Any small fragments that bind to CBS will be identified using x-ray crystallography and used as starting points to develop into larger molecules. We will then triage these potential binders against CBS and its disease mutants to determine if they act as PC molecules rescuing their functionality. The most promising small molecules can then be possible starting points for further preclinical studies in cell lines and animal models. Ultimately our proposal aims to discover small molecules as starting points for a PC therapy for classical homocystinuria.
I am incredibly honoured and excited that our proposal has been funded by the HCU Network America, as this builds on our previous work on the structural biology of CBS along with our goals to develop novel therapies for rare metabolic disorders. As such this research will leverage our group’s multi-disciplinary experience in biophysics, biochemistry, and structural-based drug screening along with guidance from our clinical contacts in the homocystinuria field.
