Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Influence of body configuration on the therapeutic effects of totally laparoscopic and laparoscopy-assisted radical total gastrectomies: a multicentre retrospective study (A report of 677 cases) / 中华消化外科杂志

Objective To investigate the influence of body configuration on the therapeutic effects of totally laparoscopic and laparoscopy-assisted radical total gastrectomies.Methods The retrospective cohort study was conducted.The clinicopathological data of 677 patients with gastric cancer who underwent laparoscopic radical total gastrectomies in the 11 clinical centers [100 patients in the First Affiliated Hospital of Army Medical University (Third Military Medical University),98 in the First Affiliated Hospital of Nanjing Medical University,94 in the First Affiliated Hospital of Nanchang University,89 in the First Affiliated Hospital of Xiamen University,81 in the Affiliated Hospital of Qinghai University,81 in the First Affiliated Hospital of Xinjiang Medical University,42 in the First Affiliated Hospital of Xi'an Jiaotong University,39 in the Traditional Chinese Medicine Hospital of Guangdong Province,26 in the First People's Hospital of Hangzhou City,17 in the Second Affiliated Hospital of Jilin University and 10 in the Xijing Hospital of Air Force Medical University (Fourth Military Medical University)] from January 2015 to June 2017 were collected.Among 677 patients,305 [89 patients in the First Affiliated Hospital of Army Medical University (Third Military Medical University),28 in the First Affiliated Hospital of Nanjing Medical University,14 in the First Affiliated Hospital of Nanchang University,26 in the First Affiliated Hospital of Xiamen University,75 in the Affiliated Hospital of Qinghai University,14 in the First Affiliated Hospital of Xinjiang Medical University,10 in the First Affiliated Hospital of Xi'an Jiaotong University,10 in the Traditional Chinese Medicine Hospital of Guangdong Province,19 in the First People's Hospital of Hangzhou City,13 in the Second Affiliated Hospital of Jilin University and 7 in the Xijing Hospital of Air Force Medical University (Fourth Military Medical University)] undergoing totally laparoscopic total gastrectomy were allocated into the totally laparoscopic group,and 372 [11 in the First Affiliated Hospital of Army Medical University (Third Military Medical University),70 in the First Affiliated Hospital of Nanjing Medical University,80 in the First Affiliated Hospital of Nanchang University,63 in the First Affiliated Hospital of Xiamen University,6 in the Affiliated Hospital of Qinghai University,67 in the First Affiliated Hospital of Xinjiang Medical University,32 in the First Affiliated Hospital of Xi'an Jiaotong University,29 in the Traditional Chinese Medicine Hospital of Guangdong Province,7 in the First People's Hospital of Hangzhou City,4 in the Second Affiliated Hospital of Jilin University and 3 in the Xijing Hospital of Air Force Medical University (Fourth Military Medical University)] undergoing laparoscopy-assisted total gastrectomy were allocated into the laparoscopy-assisted group.All patients received laparoscopic radical total gastrectomy and D2 lymphadenectomy using routine five-port method.Roux-en-Y anastomosis was applied for digestive tract reconstruction,and digestive tract reconstruction was performed under laparoscopy in the totally laparoscopic group and via upper abdominal median incision in the laparoscopy assisted group.Observation indicators:(1) surgical and postoperative situations;(2) stratified analysis:surgical and postoperative situations of obese patients [body mass index (BMI) ＞ 25.0 kg/m2,the maximum vertical distance between the anterior abdominal skin and the back skin at the level of the xiphoid bone (X-APD) ＞ an average value of 22.7 cm and X-APD/the maximum horizontal distance of a plane at a right angle to X-APD (X-TD) ＞an average value of 0.8] between groups;(3) follow-up and survival situations.Follow-up using outpatient examination and telephone interview was performed to detect the postoperative overall survival and tumor recurrence or metastasis up to July 2017.Measurement data with normal distribution were represented as x±s.Comparison between groups was analyzed by the t test.Measurement data with skewed distribution were described as M(Q),and comparison between groups was analyzed by Mann-Whithey test.Comparisons of count data were analyzed using the chi-square test.Results (1) Surgical and postoperative situations:all the patients in the 2 groups underwent successful operations,without perioperative death.Esophagojejunostomy methods of 305 patients in totally laparoscopic group:conventional circular stapler method were performed in 107 patients,antipuncture circular staplar method in 6 patients,OrVilTM method in 5 patients,functional end-to-end esophagojejunostomy method in 76 patients,peristalsis side-to-side esophagojejunostomy method in 106 patients and π esophagojejunostomy method in 5 patients.Three hundred and seventy-two patients in the totally laparoscopic group received conventional circular stapler method,including 361 with end-to-side esophagojejunostomy method and 11 with half end-to-end esophagojejunostomy method.Total operation time,time of esophagojejunostomy,length of assisted incision and using time of analgesics were respectively (235± 72)minutes,(33 ± 15)minutes,(5.6± 1.4) cm,(2.0 ± 1.2) days in the totally laparoscopic group and (223± 63) minutes,(29 ± 10) minutes,(8.0 ± 2.6) cm,(2.3 ± 1.6) days in the laparoscopy-assisted group,with statistically significant differences between groups (t =2.383,3.289,-15.236,-2.780,P ＜ 0.05).The eases with postoperative overall complications,anastomosis bleeding,anastomosis stricture,anastomosis leakage were respectively 38,6,11,11 in the totally laparoscopic group and 35,7,10,13 in the laparoscopy-assisted group,with no statistically significant difference between groups (x2 =1.621,0.007,0.470,0.006,P＞0.05).All the patients with postoperative complications were cured by symptomatic treatment.(2) Stratified analysis:length of assisted incision,using time of analgesics,time to postoperative anal exsufflation,time for initial fluid diet intake,time for initial semi-fluid diet intake,time of postoperative drainage-tube removal and duration of postoperative hospital stay in obese patients with BMI＞25.0 kg/m2,X-APD＞22.7 cm and X-APD/X-TD＞0.8 were respectively (5.9±1.3)cm,(5.7±1.4)cm,(5.6±1.4)cn,(2.0±1.2) days,(2.2±1.1)days,(2.1±1.1)days,(3.4±0.9) days,(3.3±0.9)days,(3.3±0.8)days,(4.7±1.1)days,(4.1±2.0)days,(4.0±1.6)days,(6.6±1.5)days,(6.4±2.3)days,(6.3±1.9)days,(7.8±2.3)days,(7.8±2.7)days,(7.6±2.9)days,(9±4)days,(10±5)days,(10±5) days in the totally laparoscopic group and (8.7±3.1)cm,(8.9±3.0)cm,(8.8±2.8)cm,(2.4±1.3)days,(2.5±1.5)days,(2.5±1.6)days,(3.7±1.0)days,(3.8±1.1)days,(3.7±1.3)days,(5.3±1.7)days,(4.8±1.7)days,(5.0±1.9)days,(7.4±2.3)days,(7.8±2.0)days,(7.0±2.2)days,(8.7±2.4)days,(8.4±1.9)days,(8.1±1.5)days,(1 1±8)days,(11±5)days,(1 1±5)days in the laparoscopy-assisted group,with statistically significant differences between groups (t =-7.950,-2.246,-2.222,-2.500,-2.771,-2.404,-2.251,P＜0.05).There were statistically significant differences in above indicators of patients with X-APD＞22.7 cm between groups (t =-12.089,-2.064,-3.732,-3.220,-5.297,-2.074,-2.208,P＜0.05),and in above indicators of patients with X-APD/X-TD＞0.8 between groups (t =-13.451,-2.736,-3.354,-4.961,-3.280,-2.137,-2.127,P＜0.05).(3) Follow-up and survival situations:of 677 patients,645 were followed up for 1-31 months,with a median time of 12 months,including 283 in the totally laparoscopic group and 362 in the laparoscopy-assisted group.During the follow-up,cases with overall survival,tumor recurrence and tumor metastasis were respectively 255,18 and 21 in the totally laparoscopic group and 327,25 and 20 in the laparoscopy-assisted group (11 and 10 patients in the totally laparoscopic and laparoscopy-assisted groups with simutaneous tumor recurrence and metastasis),showing no statistically significant difference between groups (x2 =0.009,0.076,0.959,P ＞ 0.05).Conclusions Totally laparoscopic and laparoscopy-assisted radical total gastrectomies are safe and feasible in obese patients,with the equivalent time of esophagojejunostomy.Totally laparoscopic radical total gastrectomy is of benefit to short-term recovery of patients.