Goessmann Gazette 2025

Researchers working to develop the next generation of drugs to treat high unmet-need diseases, including various types of cancer and Alzheimer’s disease, will soon have a new tool, an 800 MHz Nuclear Magnetic Resonance (NMR) spectrometer. Understanding the movement of biomolecules in solution, such as proteins and nucleic acids, is central to those discoveries. This high field NMR allows researchers to capture this movement at atomic resolution and will advance the research and training of many groups and students on campus. In addition, it will be accessible to various biotech companies in Massachusetts, which is particularly important, as it is the first high-field NMR in the western half of the state.

Jeanne Hardy, Professor of Chemistry and Associate Director of the IALS Models to Medicine Center, recognized the desperate need for a high-resolution NMR instrument at UMass.  Hardy, alongside Jasna Fejzo, Director of the IALS Biomolecular NMR Core Facility,  led a successful effort to obtain a $4.4 million grant from the Massachusetts Life Sciences Center (MLSC) to acquire the new spectrometer. The equipment should be installed within the next few months and will become part of the Institute for Applied Life Sciences’ (IALS) Core Facilities.

Professor Hardy’s research group used the high field NMR to study proteases but found that she and her students were waiting longer and longer to access an instrument housed at the University of Wisconsin-Madison. Hardy and her group are protein chemists who design new chemical entities to attack proteases, which are great drug targets that are currently inhibited by antiviral drugs such as Paxlovid for SARS-CoV-2 or Darunavir for HIV. Her approach to designing protease inhibitors is founded on the idea that only when one fully understands the structure and behavior (motion, range of conformations) of the proteases that they are targeting will they be able to effectively design new drugs. Structural Biology (the study of the molecular structure of proteins and other biomolecules) has been the linchpin of both biological breakthroughs and drug discovery. Hardy and other researchers anticipate that structure-guided drug design will continue to drive drug discovery for the foreseeable future. Increasingly, protein structures can be predicted by AI methods like AlphaFold and determined experimentally by cryoEM and x-ray crystallography.  However, developing the next generation of drugs requires that we understand the motions of biomolecules, such as proteins and nucleic acids, in solution.

Several Chemistry faculty plan to take advantage of the new NMR spectrometer. The new research that will be enabled by this instrument includes not only disease-relevant proteases but also proteins that are novel antibiotic targets, proteins important in neurodegeneration, next generation RNA therapeutics, and chaperones involved in protein homeostasis. The extensive biomolecular NMR expertise of Prof. Lila Gierasch, Prof. Lynmarie Thompson and their groups provide a setting on campus that will ensure that the new spectrometer is used to its fullest potential.

The new NMR spectrometer will be housed on the ground floor of LSL, and will be overseen by the Biomolecular NMR Core Facility, run by Dr. Fejzo. Dr. Fejzo has substantial experience in structural biology, drug discovery, and NMR method development. Immediately before coming to UMass Amherst, she was a laboratory head at Novartis Institutes for Biomedical Research in Cambridge, MA. Her extensive expertise in NMR methodology and biomolecular NMR has and will ensure that researchers on- and off-campus are able to optimally use the new spectrometer.

A unique aspect of the NMR spectrometer is the impact that it will have on research and development at Massachusetts-based companies. The mission of the MLSC, which funded the purchase, is to strengthen and protect Massachusetts’ leadership in the life sciences, accelerate commercialization of new treatments and therapies, create jobs, and develop the STEM workforce. To support this mission, 40% of the instrument time for the new NMR will be prioritized for industry users. Close to ten companies, ranging from large well-known businesses to smaller ventures, have expressed interest in using this new NMR because they do not have their own high-field instrument. Indeed, only four other instruments like this one exist in Massachusetts.

Presently over 300 companies are pursuing PROTAC/degraders as a transformative new drug modality that works by directly degrading (removing) disease-causing proteins. Some of these companies, such as C4 and Psivant, are already users of the IALS Mass Spectrometry facility for understanding molecular motions of their degrader projects using hydrogen-deuterium exchange mass spectrometry (HDX-MS). C4 now has four degraders in clinical trials, for Multiple Myeloma, Non-Hodgkin’s Lymphoma, Synovial Sarcoma, and other cancers. C4 Therapeutics, as well as numerous others, seek more detailed structural insights (atomic resolution by NMR vs. 5-10 amino-acid resolution by HDX-MS) into the motions of their degradation targets making next-generation degraders even more robust and selective. Such structural details could only be met by the newly acquired NMR spectrometer. 

The Chemistry Department and other departments at UMass Amherst excel in training the Massachusetts biomedical workforce. More than 1,400 BS and 110 PhD degree recipients in relevant fields graduate from UMass each year. Consequently, UMass Amherst is one of the top two producers of scientists and engineers who enter the biotech economy in the Commonwealth. Training in NMR for structural biology and other research areas, such as metabolomics, can only be meaningfully accomplished if students work with a state-of-the-art spectrometer. Acquisition of the new 800 MHz spectrometer will provide that fertile training environment for our students. Moreover, in partnership with the UMass Biotechnology Training Program, intensive 12-hour laboratory modules in NMR techniques are taught each year. These lab modules will train students to use high-field NMR instruments and collect their data independently. Such training will now be a unique feature of the education that students can obtain here at UMass Amherst. The new instrument will position Western Massachusetts as a structural biology hub, encompassing the NMR resources of UMass Amherst and the UMass Chan Medical School, and increase the competitiveness of UMass for federal funding.

Jeanne Hardy

Jeanne Hardy and her group study proteases, including caspase-6 (an Alzheimer’s Disease target) and Zika virus proteases (a Zika virus antiviral target), that are highly mobile proteins. NMR allows her group to assess the motion of these proteins and thereby develop more effective inhibitors.
 

Lila Gierasch

NMR work by Gierasch and her group has (and will) shed light on how the ubiquitous Hsp70 family members, which protect proteins from deleterious fates and chaperone their folding, may recognize their substrates. The Hsp70 chaperones ‘shop around’ the sequence of their client proteins for incompletely folded sites that carry sequence signatures indicative of their roles in folding. The chaperone binds and releases these sites, keeping them out of trouble (aggregation) but allowing them to fold.

Jianhan Chen 

High-field NMR together with multi-scale molecular modeling will allow Chen and his group to understand the structure and dynamics of the disordered C-terminal tail of alpha-synuclein within an amyloid fibril core. In this complex and crowded environment, NMR can help determine which proteins can bind to the tails and their functional roles. This is an ongoing project in collaboration with Prof. Siemer’s lab at the University of Southern California.

Craig Martin and Jasna Fejzo

Martin and Fejzo will use NMR to understand the structure and dynamics of large RNA structures. With the greater appreciation of RNA’s complex roles in biology and human physiology and the recently successful mRNA vaccines, information about the three-dimensional structures of RNA is essential. Martin’s new technology for precisely synthesizing and positioning isotopic labels in RNA will enable NMR to be applied to these incredibly important biomolecules. 

Kevin Alexander ’25 was awarded the 2024 Barry M. Goldwater Scholarship for his exceptional research accomplishments and for demonstrating a strong commitment to pursuing a career in science. He recently graduated with Bachelor’s degrees in chemistry, physics, mathematics, and astronomy. His unique academic trajectory has allowed him to tackle research problems from a variety of perspectives. His research achievements have been recognized by being awarded the J. F. B. Fund for Undergraduate Research, the Tarselli Family Research Award, the Roger G. Bates Chemistry Fund, the Sherwood-Delaney Scholarship, the Chemistry Undergraduate Research Fund, the John A. Chandler Memorial Scholarship, and two Honors Research Grants. His citizenship has also been recognized through the Senior Class Award, the Royal Society of Chemistry Certificate of Excellence, the Richard W. Fessenden Memorial Award, the Departmental Recognition Award, and the Distinguished Undergraduate TA Award.

Kevin participated in his first independent research experience in Summer 2022 under the mentorship of Jasna Fejzo and Jeanne Hardy. He used nuclear magnetic resonance (NMR) spectroscopy to study the binding kinetics of small molecules to Chikungunya virus protease nsP2. The aim of the project is to develop a treatment for Chikungunya, a mosquito-borne disease with global prevalence. More recently, he has used NMR spectroscopy to study the conformational dynamics of proteins, again with the intent of furthering progress on designing treatments for human diseases.

Kevin has participated in research outside of UMass as well. In Summer 2023, he worked at Caltech in Ryan Hadt’s lab studying electron spin relaxation mechanisms in molecular qubits via electron paramagnetic resonance spectroscopy. In Summer 2024, he worked at Harvard Medical School in Haribabu Arthanari’s lab where he used optimal control theory and spin dynamics simulations to design more efficient NMR pulse sequences.

For the next step in his career as a scientist, Kevin will pursue a PhD in chemistry at Caltech with support from the NSF-GRFP fellowship program. His research will focus on developing new techniques for spectroscopy while applying them to solve problems in physical chemistry.

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