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How Sweet It Is: GlycoSCORES Speed Drug Development

Loading TECAN: Researchers remove a sample plate from the robotic handler. With 384 sample spots (including several for calibration/calibration check), a vast number of permutations and combinations of glycosylated peptide sequences can be prepared and analyzed by the Glycosylation
Sequence Characterization and Optimization by Rapid Expression and Screening system with the result identifying which peptide sequences are most efficiently glycosylated. (Image courtesy of Northwestern University)

Courtesy Story
Defense Threat Reduction Agency’s Chemical and Biological Technologies Department

Ten years and $2.6 billion — this is the average time and cost for a new drug to go from discovery to market. Typically, clinical trials take between six to seven years alone, which can significantly delay the Department of Defense’s response to new and emerging threats. Researchers from Northwestern and Cornell Universities, in conjunction with the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department, want to change that with an innovative tool that allows for quicker therapeutic development.

Milan Mrksich, Ph.D., and Michael Jewett Ph.D., partnered with Matthew DeLisa, Ph.D., to develop the Glycosylation Sequence Characterization and Optimization by Rapid Expression and Screening (GlycoSCORES) system. This system utilizes rapid protein synthesis, glycosylation and characterization to determine the function of newly discovered proteins for accelerated drug discovery.

More and more new therapeutics are based on glycoproteins which are proteins that have sugar molecules attached to them through a process called glycosylation. These glycoproteins are promising in that they offer potential solutions to overcoming existing barriers in oral consumption and transversing the blood brain barrier for delivery.

Current methods lack the capability to characterize the enzymes that enable glycosylation. This process is significant because the addition of sugars to proteins affects how the proteins function inside the human body. It also plays a role in both biological processes and pathological conditions. Now researchers can determine the capabilities of newly discovered proteins and leverage them for the development of future therapeutics. Not only can it help us understand what a protein can be used for, it allows us to know that information quicker than previous methods – significantly quicker.

GlycoSCORES uses a high-throughput method to determine the molecular mass of the products called self-assembly monolayers for matrix-assisted desorption/ionization (SAMDI) mass spectrometry. This approach reduces the time required for protein synthesis, modification and analysis of the resulting products fifteenfold.

Further, GlycoSCORES is generalizable, allowing scientists to simultaneously change one or more variables. This allows the protein synthesis to be paired with additional protein modifications and analyzed using SAMDI. The agile, high-throughput capability allows for screening of all permutations in a shorter time period.

Highlighted in the Nature Chemical Biology journal article, “Design of Glycosylation Sites by Rapid Synthesis and Analysis of Glycosyltransferases,” the researchers describe how they selected a newly discovered protein, characterized its functionality and identified variations in protein sequence at the modification site that altered its function.

Data derived from GlycoSCORES may accelerate drug discovery and design of protein-based therapeutics to treat symptoms resulting from exposure to various naturally occurring or manufactured biological pathogens. Earlier discovery and development will help ensure therapeutics are readily available to maintain a lethal and combat-ready force.

DTRA CB POC: Revell Phillips, Ph.D.; l.r.phillips.civ@mail.mil Northwestern POC: Milan Mrksich, Ph.D.; milan.mrksich@northwestern.edu

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