RESUMO
The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered a novel class of small molecule ketobenzothiazole TMPRSS2 inhibitors with significantly improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East Respiratory Syndrome Coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice with a half-life of 8.6 hours in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.
RESUMO
This study was conducted to investigate changes of airway size, tongue and hyoid position following orthognathic surgery in mandibular prognathism, and how they are adapted to new environment in tine dependent manner. 37 patients, who had recieved orthognathic surgery, were selected for this study. lateral cephalogram of each patient was taken at preoperation, immediate postoperation, and over 6 month after operation, and were traced and analyzed. The findings of this study were as follows: 1. The size of airway was not changed at PNS and Epiglottis level after operation, but it was changed slightly at 2nd cervical vertebra level. 2. The hyoid was moved inferoposteriorly at immediate postoperation, and then it shifted toward preoperative position, but it remained slightly inferoposterior position. The distance from hyoid to genial tubercle decreased continuously. 3. The position of tongue was moved inferoposteriorly at immediate postoperation, and then it shifted toward preoperation position, but the root of the tongue remained inferoposteriorly. 4. The distance between tongue and hyoid was increased at immediate postoperation and slightly decreased during follow-up period. 5. The change of the mandibular position was not significantly correlated with changes of airway size, hyoid position, tongue morphology and tongue position.
