There have been more than 550,000 confirmed cases and over 22,000 deaths for COVID-19, the disease caused by the virus SARS-CoV-2, in the United States. Older individuals have the declined immune systems and a higher mortality from COVID-19; furthermore, there are currently no effective antiviral medications against COVID-19. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, offers emerging prevention and treatment strategies for COVID-19. SARS-CoV-2 requires host cellular factors for successful replication during infection. Targeting virus-host protein-protein interactions (PPIs) offers an effective way for the development of drug repurposing (i.e., hydroxychloroquine (HCQ), melatonin, and indomethacin) for COVID-19 as demonstrated in our recent study (Cell Discovery 2020). Supported by the NIA R01, our team are developing and implementing innovative network medicine and systems biology methodologies for drug repurposing and drug combinations. We showed that HCQ was associated with a decreased risk of coronary artery disease by reducing the expression of VCAM1 and IL-1? in human aortic endothelial cells. Exogenous melatonin administration may be of particular benefit to COVID-19 older patients given an aging-related reduction of endogenous melatonin levels. Therefore, the central unifying hypothesis of this project is that an integrative, network medicine methodology that quantifies the interplay between the virus-host interactome and drug targets in the human interactome network will offer highly repurposable drugs and clinically relevant combination regimens for effective treatment of COVID-19.
Aim 1 will test disease module hypothesis for prediction and validation of repurposable drugs for effective treatment of older individuals with COVID-19. We will utilize a network-based knowledge graph approach that incorporates not only virus-host interactions from SARS-CoV-2, but also public drug-target databases, the human protein-protein interactome, along with 24 millions of publications from PubMed database.
Aim 2 will test the hypothesis that combining anti-inflammatory and antiviral therapeutics for effective treatment of the underlying pulmonary and cardiovascular conditions in older individuals with COVID-19. We will utilize state-of-the-art pharmacoepidemiologic analyses to validate the clinical efficiency of drug combinations (i.e., melatonin plus HCQ) in reducing incidence of pulmonary and cardiovascular conditions (including acute respiratory distress syndrome, pneumonia and lung injury) in older individuals, using large-scale longitudinal Claims-Electronic Medical Record (EHR) patient databases, along with in vitro observations in human aortic endothelial cell and pulmonary arterial endothelial cell models. To reduce the confounding factors from patient databases, we will perform time-to-event pharmacoepidemiologic outcome analyses using large-scale de-identified patient EHRs from the Cleveland Clinic COVID-19 registry database. The successful completion of this project will offer clinically relevant repurposable drugs and combination regimens for COVID-19 patients with aging-related pulmonary and cardiovascular conditions. 1
There have been more than 550,000 confirmed cases and over 22,000 deaths for COVID-19, the disease caused by the virus SARS-CoV-2, in the United States. This proposed one-year supplement project will develop and apply an integrative, network medicine methodology for rapid identification of repurposable drugs and drug combinations (such as melatonin plus hydroxychloroquine) for effective treatment of older individuals with COVID-19. The successful completion of this project will minimize the translational gap between preclinical testing results and clinical outcomes, which is a significant problem in the rapid development of effective treatment approaches for the emerging COVID-19 pandemic. 1
