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.