Structural Pharmacology of the Nociceptive Ion Channel TRPM3

IARS’s Newest FARA Recipient Embarks on First Steps to Identify Better Ways to Treat Pain

Wayland Cheng, MD, PhD, 2021 Frontiers in Anesthesia Research Award (FARA) Recipient and Assistant Professor, Anesthesiology, at Washington University in St. Louis, is searching for clues to treat pain without major adverse effects through his research project on Structural Pharmacology of the Nociceptive Ion Channel TRPM3. He hopes to discover novel analgesics that would have a greater specificity for their molecular targets and fewer side effects.

With the $750,000 provided over three years by the IARS FARA, Dr. Cheng will have the support to edge closer to that goal. The first step in that journey will be for his team to understand the structure of the nociceptive ion channel, TRPM3, and the mechanisms by which small molecules regulate its function. Once uncovered, this structural information may be used to identify or design novel analgesics. “The most challenging aspect of our research is to link structural conformations of an ion channel with a specific functional state,” Dr. Cheng elucidated. “Establishing these links is essential for drug design.”

Co-Investigator for this research project, Lamees Hegazy, PhD, Assistant Professor for the Center for Clinical Pharmacology, a joint institute for the University of Health Sciences and Pharmacy in St. Louis and Washington University School of Medicine, further acknowledged this challenge. “The structure elucidation of TRPM3 is the most challenging step and it is the most rewarding as well. Because once we know the structure of the TRPM3, this opens a whole lot of opportunities for drug discovery targeting this ion channel using SBVS,” she explained. She recognized Dr. Cheng’s work ethic, professionalism and ability to set timeframes and stick to them as qualities that are important for the success of this collaborative research project.

Resourcefulness is a quality that Dr. Cheng possesses in his arsenal, which will greatly aid him in his efforts, according to Michael Avidan, MBBCh, FCA SA, Dr. Seymour and Rose T. Brown Professor of Anesthesiology, and Head of the Department of Anesthesiology at Washington University in St. Louis. He specifically credited Dr. Cheng’s ability to adopt new technologies as key to answering the most significant questions. “The most exciting aspect of Dr. Cheng’s proposal is the approach of using highly granular structural information of a nociceptive ion channel to identify drugs that may be used to treat pain. Structure-based drug design is an exciting frontier in biomedical research made accessible by new technologies in protein structure determination,” Dr. Avidan reflected. “Dr. Cheng is harnessing this approach to address a major need in medicine: treatment of pain with non-opioid analgesics.”

The FARA, the largest IARS research grant, is designed to encourage and support innovation and creativity in an individual investigator. The award funds projects with significant originality and scientific excellence. It also recognizes investigators who demonstrate commitment to research and the potential for leadership, all areas where Dr. Cheng excelled.

Dr. Cheng’s rigorous training and his unique fundamental approach were qualities that stood out to C. Michael Crowder, MD, PhD, Chair of the IARS External Advisory Board that reviewed the grant proposals. Dr. Crowder is also a previous FARA award recipient (2009). “I was most excited by the cutting edge quality of the work. The overall approach and methods proposed are simply ones that very few scientists in the world are able to accomplish, yet I’m convinced that Dr. Cheng has the training and expertise to successfully accomplish this exciting work,” Dr. Crowder stated. “Dr. Cheng has already had substantial success as an anesthesiology researcher. However, the IARS FARA will accelerate this exciting project during its relatively early stages.”

FARA reviewer Ines Koerner, MD, PhD, was also impressed by Dr. Cheng’s very distinctive and comprehensive basic-science approach to tackling a topic of enormous clinical relevance: the development of non-opiate drug alternatives for pain management. His research is comprehensive and builds on strong preliminary data and the availability of unique compounds that induce functional states of the TRPM3 receptor, according to Dr. Koerner. “Dr. Cheng is a rapidly emerging junior investigator who shows exceptional potential as a future leader in the field,” Dr. Koerner articulated. “Dr. Cheng brings tremendous relevant experience and a track record of productivity and has recruited an impressive team of collaborators, which all combine to make successful completion of this project highly likely.”

Co-Investigator and Professor of Pharmacology, Anesthesiology and Andrew C. and Barbara B. Taylor Distinguished Professor of Psychology at Washington University in St. Louis, Douglas Covey, PhD, also recognized Dr. Cheng’s novel approach, which few anesthesiologists have explored, using mass spectrometry and photoaffinity labeling to identify binding sites on receptors involved in inducing anesthesia.

The path ahead is undeniably challenging and daunting, but Dr. Cheng has the foundation, support and confidence of his collaborators and mentors behind him to succeed. “This FARA project utilizes a combination of structural, chemical biology and computational approaches, which will be essential to study the structural pharmacology of TRPM3, and Dr. Cheng is uniquely qualified to execute this research,” Dr. Avidan explained.

Dr. Cheng has built his acumen as an independent researcher through strong mentorship from leaders like Dr. Alex Evers, Former Head of Anesthesiology at Washington University, among many others, along with access to comprehensive training programs like the Washington University Anesthesiology Department’s Academic Scholars Advancement Program (ASAP) and support from previous grants and awards. In addition to being awarded the 2021 FARA, Dr. Cheng has also received a T32 training grant at Washington University and a 2017 IARS Mentored Research Award (IMRA) for his research on The Structural Basis of Neurosteroid Binding to the GABA(A) Receptor. Both awards are designed to help young investigators along in their career path. ASAP accelerates the careers of physician-scientists by combining traditional mentorship with emerging teaching and assessment modalities such as self-reflective learning and high-fidelity simulation. IMRA provides early-career anesthesiologists the support they need to take the next step in their careers.

Researchers in the Anesthesiology Department at Washington University also benefit from a highly supportive research environment including a collaborative atmosphere, strong mentorship, and experienced administrative staff, according to Dr. Avidan. All these factors contributed to Dr. Cheng’s successful research funding and his candidacy as an IARS FARA applicant. “We aspire to train and inspire leaders who will have impact on health and society beyond the specialty of anesthesiology,” Dr. Avidan relayed. “We will continue to work closely with other academic anesthesiology departments and leading academic organizations, like the IARS, to secure the future and vibrancy of anesthesiology as a flourishing and dynamic academic medical specialty.”

With his 2021 FARA research project, Dr. Cheng will play a major part of accomplishing that goal. The intent of this endeavor is to discover novel analgesics that have a greater specificity for their molecular targets and fewer side effects. “The current standard for analgesics is opioids, which have a narrow therapeutic index and major adverse effects including respiratory depression and use dependence. The prescription of opioids in the perioperative period has been a major contributor to the opioid epidemic,” Dr. Cheng explained. He is hoping that with this research he will be able to flip that paradigm.

Dr. Cheng’s attraction to this research subject dates back to his time as a graduate student where his interest was first piqued in the structure and function of ion channels. He was drawn to the remarkable capability of electrophysiologic techniques to study ion channel function at the single molecular level. As an anesthesiologist, his focus has shifted to specific ion channels, which are molecular targets of anesthetics and mediate important physiologic functions such as pain. “I am most excited about the prospects of rational drug design based on knowledge about the structure of ion channels,” Dr. Cheng revealed. “Structure-based drug design or screening has yet to be routinely successful, but this may change soon with a recent explosion of available protein structures and increasing knowledge of protein dynamics and drug binding sites.”

Dr. Cheng’s enthusiasm for this topic, coupled with his knowledge and talent as a scientist is well acknowledged among his colleagues and research contributors. “He inspires me to think about new reagents that will be of use to him in his research and also to further my own scientific interests. He is a friendly and open-minded scientist who is a delight to have as a collaborator,” expressed Dr. Covey, one of his co-investigators and a 44-year veteran at Washington University in St. Louis. “I expect great things from him as his career progresses.”

Dr. Cheng expects the IARS FARA will positively influence his research and career path. “As a junior investigator, this award will increase the recognition of my research and fund an exciting new project,” he relayed. “My hope is that this will also serve to grow our research team, foster collaborations, and allow us to reach our goal of developing novel analgesics using structure-based drug discovery.” He expressed his admiration for the inspiring physician scientists who previously received the IARS FARA and fueled him to apply for this award. “I am thrilled that the IARS chose to invest in my research program and am truly excited to see the outcome of this work,” he revealed.

The FARA award from IARS signals a great investment in Dr. Cheng and his scientific work. Dr. Avidan feels the award will add critical significance to Dr. Cheng’s research program and career and provide international recognition, which will open opportunities for collaboration in the future. “Dr. Cheng has established an exciting research program investigating ion channel structure and pharmacology,” Dr. Avidan explained. “However, Dr. Cheng is also at a relatively early stage in his scientific career when his capacity to invest in high-risk, high-reward projects is limited.” The IARS FARA will enable him to embark on such pursuits.

Obtaining this sufficient research funding to support highly impactful and cutting-edge research is no easy feat, according to Dr. Crowder. “Every specialty relies in part on private foundation grants to support some of its most promising research and researchers. The IARS FARA does this for our field,” Dr. Crowder explained. “Without it, we would lose some of our ability to compete as a specialty in performing the best medical research.”

The IARS FARA supports exceptional researchers like Dr. Cheng in tackling problems of high relevance for anesthesiology, according to Dr. Koerner. “Both Dr. Cheng and his project fit this expectation,” she stated. “This support comes at a critical stage in his career and enables him to create the fundamental data to embark on larger drug-development and translational studies.” She anticipates that his current award-winning research project will position Dr. Cheng to successfully compete for large-scale independent NIH funding for future work.

All indicators show that Dr. Cheng is gaining momentum as a physician scientist and has ambitious plans for his future and for medicine as a whole. “This award will be transformative for my research and professional trajectory,” Dr. Cheng revealed. “My goal is to be at the forefront of drug discovery with a focus on developing better analgesics and anesthetics.” With his determination and passion, there is no doubt he will be adding significant pieces to that puzzle soon.

About the Frontiers Award

The Frontiers in Anesthesia Research Award is granted triennially and is the largest IARS research grant. The FARA fosters innovation and creativity by an individual investigator, funding projects with significant originality and scientific excellence. Projects must have direct relevance to anesthesiology and play a critical role in the scientific evolution of a novel concept. For more information about the award and previous recipients, visit https://iars.org/frontiers-in-anesthesia-research-award.