Bergamottin and PAP-1 Induced ACE2 Degradation to Alleviate Infection of SARS-CoV-2.

Angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. However, inhibitors such as PAP-1 and bergamottin have been discovered; both of them can preferentially bind to ACE2, prevent RBD Spike S protein from binding to ACE2, and reduce the binding sites for RBD Spike S protein. In addition, we investigated the binding energy of PAP-1 and bergamottin with ACE2 through molecular docking with bio-layer interferometry (BLI) and found relatively high binding affinity (KD = 48.5 nM, 53.1 nM) between the PAP-1 and bergamottin groups. In addition, the nanomolar fraction had no effect on growth of the AT-II cell, but 150 µM PAP-1 and 75 µM bergamottin inhibited the proliferation of AT-II cells in vitro by 75% and 68%, respectively. Meanwhile, they significantly reduced ACE2 mRNA and proteins by 67%, 58% and 55%, 41%, respectively. These results indicate that psoralen compounds PAP-1 and bergamottin binding to ACE2 protein could be further developed in the fight against COVID-19 infection during the current pandemic. However, attention should be paid to the damage to human alveolar type II epithelial cells.

Etiology and Chinese Medicine Screening of Severe COVID-19 Based on Multiomics and Serum Pharmacology (preprint)

Background: At present, scholars believe that severe COVID-19 is related to a variety of basic diseases, and we also observe this point using multi-omics method. The latest sequencing data of severe COVID-19 patients were combined to analyze the pathological mechanism, and pharmacological experimental research on local drugs was conducted, and a compound ingredient was found to have potential medicinal value. Results Here, we observed, for patients with severe COVID-19 disease, the differential miRNA expression is mainly low but having higher expression of mRNA. These differential mRNA expressions are associated with the activation of inflammatory pathways and ultimately with hypoxia and coagulation. Using database analysis, we found that Yi Xin Tong Mai Granule(YXTMG) might regulate COVID-19 through Toll-like receptor signaling pathway by acting on different immune targets. We found a new molecular mechanism for COVID-19 to turn the crisis around, the down-regulated miR-181a-5p mediates the up-regulation of PLAU and SERPINE1 molecules to cause cardiovascular adverse events, and YXTMG may prevent it. At the same time, molecular docking indicated that the its various components have anti-inflammatory activity. In vitro studies, we confirmed that YXTMG had antioxidant and anti-inflammatory activities. Conclusions The study has supplemented the potential mechanism for the conversion of mild to critical COVID-19 disease and screened the Chinese medicines for improving these factors, providing methodological reference for disease pathology and drug development.