Research

Improving the specificity of a cancer-fighting drug

This project aims to provide an atomic-level picture of how a chemical compound works to kill cancer cells. This compound is extremely effective in eradicating cancer but has severe  side effects. A detailed picture of how it interacts with its target metabolic enzyme will provide a tool to begin decoupling its side effects from its anti-cancer properties.
supported by a grant from

Pennsylvania Department of Health       06/2020 - 05/2024

Improving the specificity of a drug targeting cancer metabolism

Understanding the biochemical basis of red blood cell remodeling in malarial infection

Infectious diseases account for two of the top ten causes of death in the US. In the developing world, it's five of ten. Malaria parasites secrete hundreds of enzymes into their host cells, modifying them to favor continued parasite growth. The goal of this project is to understand the role of a particular class of secreted enzymes called FIKK kinases. These malarial kinases modify the host red blood cell's own proteins. One aim of this project is to design inhibitors that block these kinases.

supported by

Franklin Research Grant

American Philosophical Society                                                                                                

Preventing parasites from remodeling: screening for inhibitors of kinases secreted from a malaria parasite

publications (bold = student authors)

Novak WRP, West KHJ, Kirkman LMD, Brandt GS. Re-refinement of P. falciparum orotidine 5'-monophosphate decarboxylase provides a clearer picture of an important malarial drug target. Acta Crystallographica Section F74 664 [2018]

Lin BC, Harris DR, Kirkman LMD, Perez AM, Qian Y, Schermerhorn JT, Hong MY, Winston DS, Xu L, Lieber AM, Hamilton M, Brandt GS. The anthraquinone emodin inhibits the non-exported FIKK kinase from Plasmodium falciparum. Bioorganic Chemistry 75 217 [2017]

Lin BC, Harris DR, Kirkman LMD, Perez AM, Qian Y, Schermerhorn JT, Hong MY, Winston DS, Xu L, Brandt GS. FIKK kinase, a Ser/Thr kinase important to malaria parasites, is inhibited by tyrosine kinase inhibitors. ACS Omega 2 6605 [2017]

Ocean warming and coral bleaching:
thermal effects on enzyme structure

Corals are animals that depend on intracellular photosynthetic symbionts. When the temperature of ocean water rises, the symbiosis between coral and algae breaks down. We're working with Prof Peter Fields to learn the atomic-level details of why some coral and algal GAPDH proteins are stable to heat and others aren't. 

supported by: NSF grant (Fields)
publications (bold = student authors)

Perez AM, Wolfe JA, Schermerhorn JT, Qian Y, Cela BA, Kalinowski CR, Largoza GE, Fields PA, Brandt GS. Thermal stability and structure of glyceraldehyde-3-phosphate dehydrogenase from the coral Acropora millepora. RSC Advances 11 10364 [2021]                                    PDB file  6PX2

Controlling cellular pathways with light

A typical pharmaceutical exerts its physiological effects by blocking a specific biochemical pathway in a cell. The research proposed here seeks to bring biochemical pathways under more precise experimental control, switching them on or off with pulses of light. By using photochemically active molecules, we plan to use light to dynamically turn biochemical pathways on and off. Specifically, we are targeting masked and photolabile versions of a protein kinase inhibitor.

poster (ASBMB)
Yogodzinski C, Hughes T, Brandt G. Synthesis of a photolabile inhibitor for light-dependent control of a kinase. The FASEB Journal 30 (1 Supplement): lb102 [2016

Structural variation of an enzyme across phyla

Most core metabolic processes are shared by all known life forms. For example, we humans have a set of proteins for turning sugar into energy, and so does every other organism on Earth. So, every living thing will its own a version of a particular sugar-converting enzyme. How are our enzymes different from bacterial, fungal or plant enzymes? The goal of this project is to determine the structure of versions of a single enzyme spanning the phylogenetic tree from bacteria to trees.

Since 2017, students of CHM351 have crystallized five enzymes that have never been previously structurally characterized. Refinement is underway.

Computational development of small molecules
that bind proteins

Why do things, when we have computers that could be doing them for us? 

publication

Brandt GS, Novak WR. SARS‐CoV‐2 virtual biochemistry labs on bioinformatics and drug design. Biochemistry and Molecular Biology Education 49 26  [2021]

* One of the journal's top 5 most-downloaded papers in 2022