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The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies. ImportanceSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has seriously threatened global public health and economic development. Currently, effective therapies to treat COVID-19 are urgently needed. In this study, we assessed the efficacy of the preclinical inhibitors GC376 and GS441524 using a mouse-adapted SARS-CoV-2 infected mouse model for the first time. Our results showed that low-dose combined application of GC376 and GS441524 could effectively protect mice from HRB26M infection in the upper and lower respiratory tracts. Hence, the combined application should be developed and considered for future clinic practice.
ABSTRACT
Coronaviruses that infect humans belong to the Alpha-coronavirus (including HCoV-229E) and Beta-coronavirus (including SARS-CoV and SARS-CoV-2) genera. In particular, SARS-CoV-2 is currently a major threat to public health worldwide. However, no commercial vaccines against the coronaviruses that can infect humans are available. The spike (S) homotrimers bind to their receptors through the receptor-binding domain (RBD), which is believed to be a major target to block viral entry. In this study, we selected Alpha-coronavirus (HCoV-229E) and Beta-coronavirus (SARS-CoV and SARS-CoV-2) as models. Their RBDs were observed to adopt two different conformational states (lying or standing). Then, structural and immunological analyses were used to explore differences in the immune response with RBDs among these coronaviruses. Our results showed that more RBD-specific antibodies were induced by the S trimer with the RBD in the "standing" state (SARS-CoV and SARS-CoV-2) than the S trimer with the RBD in the "lying" state (HCoV-229E), and the affinity between the RBD-specific antibodies and S trimer was also higher in the SARS-CoV and SARS-CoV-2. In addition, we found that the ability of the HCoV-229E RBD to induce neutralizing antibodies was much lower and the intact and stable S1 subunit was essential for producing efficient neutralizing antibodies against HCoV-229E. Importantly, our results reveal different vaccine strategies for coronaviruses, and S-trimer is better than RBD as a target for vaccine development in Alpha-coronavirus. Our findings will provide important implications for future development of coronavirus vaccines. ImportanceOutbreak of coronaviruses, especially SARS-CoV-2, poses a serious threat to global public health. Development of vaccines to prevent the coronaviruses that can infect humans has always been a top priority. Coronavirus spike (S) protein is considered as a major target for vaccine development. Currently, structural studies have shown that Alpha-coronavirus (HCoV-229E) and Beta-coronavirus (SARS-CoV and SARS-CoV-2) RBDs are in lying and standing state, respectively. Here, we tested the ability of S-trimer and RBD to induce neutralizing antibodies among these coronaviruses. Our results showed that Beta-CoVs RBDs are in a standing state, and their S proteins can induce more neutralizing antibodies targeting RBD. However, HCoV-229E RBD is in a lying state, and its S protein induces a low level of neutralizing antibody targeting RBD. Our results indicate that Alpha-coronavirus is more conducive to escape host immune recognition, and also provide novel ideas for the development of vaccines targeting S protein.
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Objective To study the topical application of Tuhuai decoction and its disassembled prescriptions on skin function of mice with epidermal hyperplasia, and to provide a theoretical basis for the treatment of psoriasis. Methods According to the Denda method, skin barrier function in mice was destructed with tape, to produce epidermal hyperplasia model. Tuhuai decoction and its disassembled prescriptions with different concentrations of water and alcohol extracts were external applied on the mice. Since the beginning of the treatment, loss of skin moisture of both sides the trunk was detected with Multi-functional instrument at every day before using the medicine. Results Tuhuai decoction had function of reducing the amount of water loss of skin. The disassembled prescriptions, such as Angelica group, safflower group, Danshen root group, and water and ethanol extracts of Prtmella group can reduce the amount of water loss of skin effect. Conclusion Water and ethanol extracts of Tuhuai decoction has the functions of reducing water loss of skin and resisting hyperplasia,suitable for treating psoriasis by external application, setting a foundation for clinical treatment of psoriasis.
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Objective To study the effects of treating herpes zoster with the combination of Chinese and western medicine.Methods 160 cases of herpes zoster were randomly recruited into a treatment group(n=80),and a control group (n=80).The control group was treated with westem medicine(acyclovir,ethacridine solvents,and vitamin B6 and B12).The treatment group was administrated with Chinese medicines,acupuncture and cupping on the basis of treats in the control group Results The total effective rate was 100%in the treatment group and 72.5%in the control group.There was significant difference between the two groups(χ~2=23.85,P＜0.05).Conclusion The combination of Chinese and western medicine is effective in treating herpes zoster and worthy of generalization.
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Objective:To observe the effect of internal and external use of Chinese material medica with syndrome differentiation on acne vulgaris.Methods:200 patients with acne vulgaris were randomly divided into treatment group(110 cases)and control group(90 cases).Treatment group were given acne facial mask,oral medicine decoction,and the control group were treated with13-cis-Retinoic Acid Capsules,topical Clindamycin Gel,7 weeks for a course of treatment,the clinical effect were compared.Results:The effect on facial lesion in treatment group and control group had significant difference(P
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1), attributable risk (AR)=13.33%; ⑤Even though the serum specimens were taken from PB patients, the Ab of majouity of patients converted to positive when relapse occurred. In the majority of patients relapsed the levels of IgM-AbL tended to be increasing or pesistently positive. Usually relapse occurred 1-2 years after IgM-AbL was converted to positive. Relapse occurred 11-30 years after the patients were cured. In very rare case downgrading(from tuberculous to borderline leprosy) occurred. ⑥The levels of IgM-AbL gradually decreased in all relapsed patients after effective treatment except one case whose IgM-AbL was persistently positive. Conclusions The above results indicate that the ND-ELISA might be useful in screening early M.leprae infection and in predicting and monitoring the relapse of leprosy, especially in multibacillary patients.
