New York Blood Center Enterprises (NYBCe) is perhaps best known for being one of the nation’s largest independent blood centers — however, the nonprofit’s expertise extends far beyond blood collection and distribution.
With the help of the Lindsley F. Kimball Research Institute (LFKRI), NYBCe also conducts groundbreaking research in transfusion medicine, epidemiology, hematology, cell therapy, and infectious disease. This work has a direct humanitarian impact, improving patient outcomes on a local, national, and international scale.
Over the Enterprise’s 50-year legacy, LFKRI investigators have published over 4,000 scholarly articles in scientific journals in collaboration with colleagues at world-renowned institutions. Through these partnerships as well as numerous landmark patents and licenses, NYBCe continuously shapes the landscape of global healthcare and scientific discovery.
One of LFKRI’s investigators is Asim K. Debnath, PhD. Dr. Debnath has been with the Enterprise for 28 years and is currently the Head of the Laboratory of Molecular Modeling and Drug Design. Recently, he and his team published an article titled, “Stapled peptides based on Human Angiotensin-Converting Enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro” — has since been published in mBio.
In this study, the Laboratory of Molecular Modeling and Drug Design designed four peptides, which were constrained by two synthetic braces (called staple) to maintain α-helicity. Three of the four peptides showed potent inhibition in a single-cycle virus inhibition assay. The linear peptide, used as a control, did not show any α-helicity and antiviral activity. The most active peptide also showed high stability in human plasma.
Dr. Debnath recently sat down with NYBCe to speak more about this project as well as his work with NYBCe and LFKRI.
Q: In your research, your team investigated four stapled peptides’ and their potential ability to prevent SARS-CoV-2, the coronavirus that causes COVID-19, from causing infection in human cells. In layman’s terms, can you briefly explain the mechanism of action you investigated? What are stapled peptides, and how would they prevent the virus from infecting cells?
Dr. Debnath: SARS-CoV-2 that causes COVID-19 requires to enter human cells for continuing its lifecycle. For that, the virus needs to bind to a human cell protein, termed receptor. SARS-CoV-2 utilizes Human Angiotensin-Converting Enzyme 2 (ACE2) as a receptor. The virus uses its spike protein.
We hypothesized that if we can create a decoy of ACE2 representing the binding site peptide — which is α-helical, smaller, and drug-like — the virus can be “fooled” into binding with this small part of ACE2 protein, thereby preventing the virus from binding to the ACE2 receptor. However, a small peptide loses its conformation when separated from the protein.
The stapled peptides are typically derived from an α-helix of the binding interface and are locked into bioactive structures by using chemical linkers like a staple. Stapling helps to maintain the α-helical conformation, improve stability against digestion by proteolysis, and improve biological activity. We designed four stapled peptides based on the α-helical binding region of ACE2.
Q: Out of all the possible fields of research related to COVID-19 and SARS-CoV-2, what drew you to this one? Did your history with HIV research influence this project?
Dr. Debnath: For the last 20 years, my group has been involved in designing HIV entry/fusion inhibitors. We made enormous progress in this field. Since SARS-CoV-2 also uses a similar mechanism to bind and fuse with human cells, we thought that during the pandemic, and due to the urgent need to develop therapeutics, we should use our expertise in HIV research to develop drugs against COVID-19.
Q: How long have you and your team been conducting this research? Did you begin as soon as the pandemic began, or did it take some time to lay groundwork?
Dr. Debnath: We started researching and developing drugs that fought against COVID-19 in April of 2020. It took some time to lay the groundwork and get the necessary funds. However, I am pleased to say that Dr. Christopher Hillyer, NYBCe’s President and CEO, valued our approach, found the potential, and provided funding for this research.
Q: Ideally, what implications or impact do you think this research could have for patients who are at risk of developing severe COVID-19?
Dr. Debnath: We believe that the entry/fusion inhibitors we’re trying to develop will help both as prophylactic and therapeutic in preventing people from getting a severe disease from COVID-19 because these molecules prevent the virus from entering human cells.
Q: Are you planning to move on to other research next, or do you have next steps for this project? If so, what are they?
Dr. Debnath: We are continuously trying to improve the efficacy and safety of the stapled peptides as COVID-19 inhibitors. However, lately, we’ve identified several small-molecule inhibitors that show potent and broad-spectrum inhibition against other coronaviruses such as SARS-CoV, MERS-CoV and SARS-CoV-2. We are planning to file a patent soon and publish it in a journal.
Q: How has conducting your research via NYBCe and LFKRI propelled your research forward?
Dr. Debnath: LFKRI and NYBCe helped build my research career and moved my research on HIV-1 drug discovery forward tremendously. The collaboration opportunity within LFKRI was excellent, evident in my research publications and also in filing patents.
Q: How can the general audience help support your research?
Dr. Debnath: The general audience can read about our research and familiarize themselves with the contributions that NYBCe and LFKRI made focusing on human health. They may also help to publicize our research and can make philanthropic contributions.
NYBCe relies on financial contributions to support their life-saving mission and continue the fight against COVID-19.
To support Dr. Debnath and other LFKRI investigators, please consider donating online now. You can make contributions on a one-time or recurring basis or give on behalf of an organization or in memory of a loved one. For more on NYBCe’s philanthropic needs, contact the Office of Philanthropy directly by filling out this form.