Loren Walensky, MD, PhD
Principal Investigator and Attending Physician, Department of Pediatric Oncology, Dana-Farber
A technology that originated at the Dana-Farber Cancer Institute has led to the development of antiviral drugs with the potential to block SARS-CoV-2, the virus responsible for COVID-19, in addition to other viruses that cause life-threatening human infections. The approach is currently being evaluated as a nasal spray that people can self-administer after testing positive for SARS-CoV-2. The research performed in the laboratory of Loren Walensky, MD, PhD, Principal Investigator in the Department of Pediatric Oncology at Dana-Farber and Professor of Pediatrics at Harvard Medical School, involved the design of stapled lipopeptides that inhibit a specific viral protein from attaching to human cells at the sites of infection. The platform was licensed to Red Queen Therapeutics, Inc., a clinical-stage company that recently completed a successful clinical trial using the compound from Walensky’s lab.
Targeting Viral Entry with Stapled Lipopeptides
The concept for this therapy originated nearly two decades ago, when Walensky and Gregory Bird, PhD, of the Department of Pediatric Oncology at Dana-Farber, focused on the process by which the human immunodeficiency virus (HIV-1) causes infection. Viruses like HIV-1 infect cells by forming a six-helix bundle that fuses with the host’s cell membranes. To counter this, Walensky and Bird aimed to use their peptide ‘stapling’ technology to reinforce the biologically active structure of a key helical domain involved in the fusion process, addressing previous challenges such as the rapid degradation of peptides (strings of amino acids) in the body. The strategy was successful and blocked infection by HIV-1, including drug-resistant strains.
“Having achieved proof-of-concept for stapling a fusion helix of HIV-1 to block infection, we extended the work to treat other viruses that use the same mechanism to infect cells,” Walensky explains. By 2014, the team succeeded in developing inhibitors of respiratory syncytial virus (RSV) and showed that they could both prevent infection in the nose and block the spread of infection from nose to lungs, which is the cause of serious illness in infants, the elderly and immunocompromised patients. When the COVID-19 pandemic hit in 2020, Walensky recognized the urgency of leveraging his stapling approach to develop an inhibitor of the SARS-CoV-2 virus.
Adapting the Platform for COVID-19
“When everything shut down, we were fortunate to receive permission for a skeleton crew to continue working to create a SARS-CoV-2 therapeutic that could be administered on-demand to prevent disease and reduce transmission. We knew from our prior work with HIV-1 that the stapled peptides remained active against mutant strains, and this turned out to be true for SARS-CoV-2 variants as well,” he notes.
Walensky collaborated with Robert Davey, PhD, of Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) to test his lab’s compounds in specialized facilities approved to handle dangerous viruses like SARS-CoV-2. Davey’s team found that the compounds were highly active against SARS-CoV-2 and its variants. “Once we had lead compounds in hand, we turned to the National Institute of Allergy and Infectious Diseases (NIAID) for help in getting them tested in animal models,” Walensky says. “We were fortunate to be linked to Richard Bowen, PhD, at Colorado State University, where nasal administration of our drug candidate was found to be effective at preventing and treating SARS-CoV-2 infection in hamsters.”
“Using [the nasal spray] before an important but high-risk gathering could reduce infection risk, while early use after exposure or a positive test could help lower viral load, reduce symptoms and limit spread to others.”
Loren Walensky, MD, PhD
The Case for Stapled Lipopeptide Treatment of COVID-19
By interfering with viral entry into cells, stapled lipopeptides not only have the potential to prevent infection and disease progression, but also to accelerate the body’s efforts to clear the virus and thus decrease transmission (preventing the virus from spreading to others). The overall goal is to prevent people from becoming ill from COVID-19. The stapled lipopeptide approach is unique because it provides rapid, real-time protection against infection without the delay required for vaccines to take effect. Unlike oral systemic treatments, it works locally to block the virus at the site of entry. This could be particularly beneficial for immunocompromised individuals who cannot get vaccinated or tolerate oral regimens.
“Our strategy could offer on-demand protection—whether you’re gearing up for a big event, have been exposed to someone who tested positive for COVID-19 or just tested positive yourself,” Walensky explains. “Using it before an important but high-risk gathering could reduce infection risk, while early use after exposure or a positive test could help lower viral load, reduce symptoms and limit spread to others.”
His team published the findings of their research in January 2024 in Nature Communications, confirming that their lead compound was effective in blocking a broad spectrum of SARS-CoV-2 variants and preventing and treating infection in hamsters.
Leveraging Collaborations to Drive the Research Forward
Walensky credits the success of his laboratory’s efforts to the collaborations and essential funding opportunities that enabled the work to progress—even in the midst of a public health crisis.
“One of the biggest challenges in academic drug development is transitioning worthy projects from the academic setting to real-world application. Red Queen Therapeutics and its founding venture investor Apple Tree Partners played a crucial role in making that possible. They provided the funding and expertise to transform our lead stapled lipopeptide into a nasal spray that could be delivered to patients in record time,” Walensky emphasizes.
“It is remarkable to think that the seeds for this potential breakthrough were planted as part of my postdoctoral training at Dana-Farber in Loren’s lab, and now after years of focus and persistence, we are seeing our compounds progress through clinical trials,” Bird reflects.
In addition to support from Dana-Farber and NIAID’s preclinical testing program for Walensky’s work, the studies conducted by the Davey lab were funded by the Massachusetts Consortium on Pathogen Readiness and the National Institutes of Health.
Advancing Public Health
Red Queen recently completed a Phase 1 trial of RQ-01, the stapled lipopeptide inhibitor of SARS-CoV-2, in patients who tested positive for COVID-19. This first-of-its-kind study demonstrated both safety and preliminary activity in accelerating viral clearance. Next steps will include expanded clinical testing and advancing a spectrum of stapled lipopeptides to combat other serious infections, including RSV and influenza.
“Now that we have seen clinical proof of concept for Red Queen’s stapled lipopeptide technology, we are excited to move forward with developing treatments for COVID-19 and other endemic or emerging pandemic diseases, including new influenza strains,” said Red Queen CEO Mark Mitchnick, MD. “As scientific advisors to the company, Loren and Gregory have been great to work with, and we look forward to continuing our collaboration to deliver important new options for combating infectious diseases.”
Stapled lipopeptides are exceptionally stable, transportable at room temperature, and can be self-administered, enabling potential deployment worldwide to combat emerging public health threats. Red Queen is also exploring a nebulized formulation for direct inhalation into the lungs to prevent or treat respiratory infections.
“Red Queen’s platform is well positioned to expand antiviral treatment options and improve accessibility for underserved populations,” Walensky says. Now, Walensky and Red Queen are focused on further developing and validating this new drug modality, which carries the potential to curb infectious disease threats and help contain pandemics at their onset.
Team Members
Gregory Bird, PhD
Senior Scientist, Pediatric Oncology, Dana-Farber Cancer Institute
