key: cord-215345-p1iktm9v authors: He, Bing; Garmire, Lana title: Prediction of repurposed drugs for treating lung injury in COVID-19 date: 2020-03-30 journal: nan DOI: nan sha: doc_id: 215345 cord_uid: p1iktm9v Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, brought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Inhibition of Angiotensin-converting enzyme 2 (ACE2) caused by spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19, based on their abilities to reverse the gene expression patterns in HCC515 cells treated with ACE2 inhibitor and in human COVID-19 patient lung tissues. Further bioinformatics analysis shows that twelve significantly enriched pathways (P-value<0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues, including signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and Chemokine signaling pathways. All these twelve pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares eleven of twelve pathways with COL-3 with common target genes such as RHOA. It also uniquely targets genes related to lung injury, such as CALR and MMP14. In summary, this study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have the potential as repurposed drugs for its treatment. Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world, resulting in more than 0.3 million infections and over fourteen thousand deaths by now. It is causing tens of thousands of new infections and thousands of mortalities every day. Severe viral pneumonia related lung injury with respiratory failure is the main reason of COVID-19 related death 1 . This novel coronavirus (CoV), termed severe acute respiratory synrdrome (SARS)-CoV-2, uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and the serine protease TMPRSS2 for S protein priming 2 . In SARS-CoV infection, viral spike protein inhibits ACE2 and causes severe lung injury 3, 4 . Since the spike protein of (SARS)-CoV-2 interacts with ACE2 as does the spike protein of SARS-CoV, inhibition of ACE2 may be the pathogenic mechanism in (SARS)-CoV-2 induced lung injury. Based on this assumption, we performed drug reposition analysis to identify drugs and compounds for treating (SARS)-CoV-2 induced lung injury. We collected differential gene expression profiles in HCC515 and A549 lung cells with the inhibition of ACE2 from LINCS L1000 project 5 . Then we analyzed 12,707 drugs and compounds from LINCS L1000 pharmacogenomics data to find best candidates that could reverse abnormal gene In lung, the inhibition of ACE2 promote lung injury via the renin-angiotensin system (RAS) 6 . In pulmonary RAS, ACE2 converts angiotensin II (Ang II), an octapeptide hormone, to Ang-(1-7), an heptapeptide hormone. Ang II is a pulmonary profibrotic mediator and stimulates procollagen production in lung fibroblasts to promote lung injury 7 . Ang-(1-7) protects lung from injury, through reducing both inflammatory response by lowering cytokine release 8 and pulmonary fibrosis by inhibiting fibrotic signaling pathways 9 . Thus, inhibition of ACE2 will increase Ang II level and decrease Ang-(1-7), promote fibrosis and inflammation and injure lung tissues (Figure 1 ). Among proposed candidate drugs, panobinostat and trichostatin-a were shown to inhibit pulmonary fibrosis 10, 11 , while geldanamycin, COL-3 and narciclasine inhibit inflammation 12-14 , to attenuate lung injury in animal model (Figure 1 ). Panobinostat is a hydroxamic acid and can act as a non-selective histone deacetylase (HDAC) inhibitor. It was approved for the treatment of multiple myeloma. Panobinostat was reported to reduce pulmonary fibrosis by inducing cell cycle arrest and apoptosis in idiopathic pulmonary fibrosis fibroblasts 10 . Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian HDACs, but not class III HDACs. It attenuated lung injury in various diseases 15, 16 . Geldanamycin is an inhibitor of heat shock protein 90. It reduced H5N1 infection induced lung injury 12 In summary, we propose the six candidate drugs above, which could be used to inhibit pulmonary fibrosis or inflammation and thus attenuate lung injury induced by (SARS)-CoV-2. It is our hope to solicit the interest of the biomedical community, to save more lives from severe respiratory failure in COVID-19. We downloaded level 5 LINCS L1000 data, a collection of gene expression profiles for The differential gene expression of 12,328 genes, simulating (SARS)-CoV-2 related inhibition of ACE2 in lung, were transformed to a gene rank list. The reference dataset contains gene rank lists of treatments of 12,707 drugs from LINCS L1000 data as mentioned above. In our hypothesis, an effective drug treatment is one that reverts the aberrant gene expression back to the normal levels. Therefore, an outlier-sum (OS) based statistic was used to model the overall disease-drug connectivity by aggregating disease transcriptome changes with drug perturbation using DrInsight Package 17 . The Kolmogorov-Smirnov (K-S) test was used determine whether the OS from one drug is larger than those from the rest drugs and compounds in the reference dataset. The false discovery rate (FDR) method was used to adjust P-values from the K-S test to avoid false discovery in multiple comparisons. A drug with FDR<0.05 was selected as the candidate drug for the disease. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles Angiotensin-converting enzyme 2 in lung diseases Angiotensin II and the fibroproliferative response to acute lung injury The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-kappaB pathway Comparison of the antifibrotic effects of the pan-histone deacetylaseinhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis Prevention of Pulmonary Fibrosis via Trichostatin A (TSA) in Bleomycin Induced Rats Geldanamycin Reduces Acute Respiratory Distress Syndrome and Promotes the Survival of Mice Infected with the Highly Virulent H5N1 Influenza Virus Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model Narciclasine improves outcome in sepsis among neonatal rats via inhibition of calprotectin and alleviating inflammatory responses Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway Histone deacetylase inhibitors trichostatin A and suberoylanilide hydroxamic acid attenuate ventilator-induced lung injury Breaking the paradigm: Dr Insight empowers signature-free, enhanced drug repurposing This research was supported by grants K01ES025434 awarded by NIEHS through funds provided by the trans-NIH Big Data to Knowledge (BD2K) initiative (www.bd2k.nih.gov), R01LM012373 and R01 LM12907 awarded by NLM, and R01 HD084633 awarded by NICHD to L.X. Garmire. All the codes and data are available at: https://github.com/lanagarmire/COVID19-Drugs-LungInjury The authors declare no competing financial interests.