ABSTRACT
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.
Subject(s)
Animals , Humans , Mice , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Influenza A virus , Leflunomide , Pharmacology , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus ReplicationABSTRACT
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.
Subject(s)
Animals , Humans , Mice , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Influenza A virus , Leflunomide , Pharmacology , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus ReplicationABSTRACT
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.
Subject(s)
Animals , Humans , Mice , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Influenza A virus , Leflunomide , Pharmacology , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus ReplicationABSTRACT
Objective To improve the accuracy of diagnosis and differential diagnosis by summarizing imaging characteristics of spinal giant cell tumor of bone (GCTB).Methods Total 28 cases of spinal GCT were confirmed by pathology,of which 2 localized in cervical vertebra,8 in thoracic vertebra,8 in lumbar vertebra,and the other 10 lesions in the sacrum.All patients underwent X-ray,CT,and MRI scanning.Results (1)The incidence of spinal GCTB in the sacrum is highest,up to 35.7%.Lesions can locate in single or more vertebral bodies.All of the 10 cases with primary lesion locating the sacrum were involved in more vertebral bodies. (2)X-ray and CT showed central or eccentric vertebral destruction with 22 cases involving in adnexal bones,21 cases with bone crest or bony septum and 26 cases with soft tissue mass.(3)Lesions examined with MRI showed inhomogeneous isointense or slight hy-pointense on T1 WI,inhomogeneous hyperintense or isointense on T2 WI and inhomogeneous hyperintense or slight hyperintense on STIR.(4)Expansive bone destruction and soft tissue mass occurred again in postoperative recurrent lesions.Conclusion X-ray,CT and MRI are of significant value in the diagnosis of the spinal GCT.The combination of the three is helpful to improve the accuracy of diagnosis and differential diagnosis.
ABSTRACT
Objective To investigate the imaging features of dysplasia epiphysealis hemimelica (DEH).Methods Thirteen cases of DEH confirmed by pathology (between 1.5 to 19.0 years old)underwent X-ray scan.Additionally,CT scan was performed in one patient,MR scan was performed in one,and CT and MR scan were both performed in one.Results The lesions all occurred in lower limb.There were 32 lesions,and multiple lesions were detected in 8 cases.Lesions involved holo-epiphyses in 6 cases,Twenty-three lesions were in the medial limbs,3 were in the lateral limb.With Azouz classification,the limited form was identified in 5 cases,while the classic form was identified in 8 cases.Among 13 cases,there were 4 cases with ankle eversion,3 cases with the knock knee,2 cases with the ankle inversion,and 2 cases with the strephexopodia.The metaphysis of 8 cases were widened and deformed,and the provisional zone of calcification of 1case disappeared partly and the epiphysis closed prematurely.Conclusions One or multiple eccentric enlarged ossification center of unilateral or bilateral limb is the imaging feature of DEH.There is sporadic calcification or ossification on the prophase.The calcification or ossification can fuse each other to form agglomerate at the advanced stage.The bone can deform and shift when compressed by the mass,and bone defect can even occur.
ABSTRACT
Objective To explore the imaing features of hemangioma in the long bone and improve the diagnostic level of this disease. Methods The X-ray(14 cases), CT(9 cases) and MRI(6 cases)findings of 18 patientswith histologically proven hemangioma in the long bone after surgery were retrospectively reviewed. Results Ten tumors occurred in medullary cavity or bone end(medullary type),6 on the surface of bone (periosteal type) and 3 in cortex (intracortical type). X-ray findings: among 8 cases of medullary type, 3 showed honeycomb appearance, 3 lytic areas with sclerotic borders, one purely osteolyticchanges, and 1 frosted glass; 3 cases of periosteal type showed sclerosis and thickening of the underlying cortex; 3 cases of intracortical type showed well-defined osteolytic foci. CT findings: among 6 cases of medullary type, 5 appeared as expansile lytic lesion with uneven selerotic rim (3 cases)orhoneycomb appearance (2 cases), 1 cribriform appearance in the cortical bone, 2 periostealnew bone formation in vertical radiation pattern; 1 ground-glass appearance; among 2 cases of periosteal typeone showed regular cortical thickening, and the other irregular periosteal proliferation with marrowing of medullarycavity; 1 case of intracorticaltype showed density similar to that of soft tissue, with cortical thickening and expansion . MRI findings: 2 apeared as well-defined lesions with low signal intensity on T1WI and high signal intensity on T2WI; 1 appeared as ill-defined lesion with low to intermediate signal intensity on T1 WI and T2 WI. One showed breakthrogh of cortex and formation of soft tissue mass with low signal intensity on T1 WI and high signal on T2WI. Two showed thickening of periosteumwith intermediate signal intensity in one of them and very low signal intensity in the other. Two showed abnormal signal intensity in surrounding muscles, which was high on T2 WI and intermediate on T1 WI. Conclusions The soap-bubble or honeycomb appearance is the typical radiographic finding of hemangioma in long bone. CT and MRI can provide useful information for the diagnosis of hemangioma in long bone.