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1.
Antimicrob Agents Chemother ; 65(8): e0035021, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1486470

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Neutralizing , Antibodies, Viral , China , Double-Blind Method , Humans
2.
Acta Pharmacol Sin ; 43(4): 788-796, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1343437

ABSTRACT

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , COVID-19/drug therapy , Humans , Protein Binding , SARS-CoV-2
3.
Nat Commun ; 12(1): 3623, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1270656

ABSTRACT

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.


Subject(s)
Coronavirus 3C Proteases/drug effects , Pyrogallol/chemistry , Pyrogallol/isolation & purification , Pyrogallol/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases , Drug Design , Flavonoids , HEK293 Cells , Humans , Kinetics , Ligands , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry
4.
Antimicrob Agents Chemother ; 65(8): e0035021, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1223556

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Neutralizing , Antibodies, Viral , China , Double-Blind Method , Humans
5.
Medicine (Baltimore) ; 100(1): e24151, 2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1072466

ABSTRACT

ABSTRACT: Coronavirus disease 2019 (COVID-19) is still developing worldwide. The prognosis of the disease will become worse and mortality will be even higher when it is combined with cardiovascular disease. Furthermore, COVID-19 is highly infectious and requires strict isolation measures. For acute coronary syndromes (ACS), a common cardiovascular disease, infection may aggravate the occurrence and development of ACS, making the management of more difficult. It will be an enormous challenge for clinical practice to deal with ACS in this setting of COVID-19.Aim to reduce the mortality of ACS patients during the epidemic of COVID-19 by standardizing procedures as much as possible.Pubmed and other relevant databases were searched to retrieve articles on COVID-19 and articles on ACS management strategies during previous influenza epidemics. The data was described and synthesized to summarize the diagnosis and management strategy of ACS, the preparation of catheter laboratory, and the protection of the medical staff in the context of COVID-19. Ethical approval is not required in this study, because it is a review with no recourse to patient identifiable information.Standardized diagnosis and treatment advice can help reduce the mortality of COVID-19 patients with ACS. In the absence of contraindications, the third generation of thrombolytic drugs should be the first choice for thrombolytic treatment in the isolation ward. For patients who have to receive PCI, this article provides detailed protective measures to avoid nosocomial infection.


Subject(s)
Acute Coronary Syndrome/therapy , Acute Coronary Syndrome/virology , COVID-19/epidemiology , Cross Infection/prevention & control , Infection Control/standards , Pneumonia, Viral/epidemiology , Acute Coronary Syndrome/mortality , COVID-19/transmission , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
6.
Int J Infect Dis ; 100: 141-148, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-943161

ABSTRACT

OBJECTIVES: We aimed to explore the effect of antiretroviral treatment (ART) history on clinical characteristics of patients with co-infection of SARS-CoV-2 and HIV. METHODS: We retrospectively reviewed 20 patients with laboratory-confirmed co-infection of SARS-CoV-2 and HIV in a designated hospital. Patients were divided into medicine group (n = 12) and non-medicine group (n = 8) according to previous ART history before SARS-CoV-2 infection. RESULTS: The median age was 46.5 years and 15 (75%) were female. Ten patients had initial negative RT-PCR on admission, 5 of which had normal CT appearance and 4 were asymptomatic. Lymphocytes were low in 9 patients (45%), CD4 cell count and CD4/CD8 were low in all patients. The predominant CT features in 19 patients were multiple (42%) ground-glass opacities (58%) and consolidations (32%). Erythrocyte sedimentation rate (ESR) in the medicine group was significantly lower than that in the non-medicine group [median (interquartile range, IQR):14.0 (10.0-34.0) vs. 51.0 (35.8-62.0), P = 0.005]. Nineteen patients (95%) were discharged with a median hospital stay of 30 days (IQR, 26-30). CONCLUSIONS: Most patients with SARS-CoV-2 and HIV co-infection exhibited mild to moderate symptoms. The milder extent of inflammatory response to SARS-CoV-2 infection might be associated with a previous history of ART in HIV-infected patients.


Subject(s)
Anti-Retroviral Agents/therapeutic use , Betacoronavirus , Coinfection/complications , Coronavirus Infections/complications , HIV Infections/drug therapy , Pneumonia, Viral/complications , Adult , COVID-19 , Coinfection/drug therapy , Female , Humans , Length of Stay , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2
7.
Acta Pharmacol Sin ; 41(9): 1167-1177, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-691161

ABSTRACT

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections , Drugs, Chinese Herbal , Flavanones , Flavonoids , Pandemics , Pneumonia, Viral , Virus Replication/drug effects , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/physiology , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Enzyme Assays , Flavanones/chemistry , Flavanones/pharmacokinetics , Flavonoids/chemistry , Flavonoids/pharmacokinetics , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Vero Cells , Virus Replication/physiology
8.
Chin J Traumatol ; 23(4): 196-201, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-601868

ABSTRACT

Outbreak of COVID-19 is ongoing all over the world. Spine trauma is one of the most common types of trauma and will probably be encountered during the fight against COVID-19 and resumption of work and production. Patients with unstable spine fractures or continuous deterioration of neurological function require emergency surgery. The COVID-19 epidemic has brought tremendous challenges to the diagnosis and treatment of such patients. To coordinate the diagnosis and treatment of infectious disease prevention and spine trauma so as to formulate a rigorous diagnosis and treatment plan and to reduce the disability and mortality of the disease, multidisciplinary collaboration is needed. This expert consensus is formulated in order to (1) prevent and control the epidemic, (2) diagnose and treat patients with spine trauma reasonably, and (3) reduce the risk of cross-infection between patients and medical personnel during the treatment.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Practice Guidelines as Topic , Spinal Injuries/diagnosis , Spinal Injuries/therapy , COVID-19 , Coronavirus Infections/prevention & control , Cross Infection/prevention & control , Emergency Service, Hospital , Humans , Pandemics/prevention & control , Patient Care Team , Pneumonia, Viral/prevention & control , SARS-CoV-2 , Transportation of Patients
9.
Knee Surg Sports Traumatol Arthrosc ; 28(7): 2027-2035, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-592102

ABSTRACT

PURPOSE: It was the primary purpose of the present systematic review to identify the optimal protection measures during COVID-19 pandemic and provide guidance of protective measures for orthopedic surgeons. The secondary purpose was to report the protection experience of an orthopedic trauma center in Wuhan, China during the pandemic. METHODS: A systematic search of the PubMed, Cochrane, Web of Science, Google Scholar was performed for studies about COVID-19, fracture, trauma, orthopedic, healthcare workers, protection, telemedicine. The appropriate protective measures for orthopedic surgeons and patients were reviewed (on-site first aid, emergency room, operating room, isolation wards, general ward, etc.) during the entire diagnosis and treatment process of traumatic patients. RESULTS: Eighteen studies were included, and most studies (13/18) emphasized that orthopedic surgeons should pay attention to prevent cross-infection. Only four studies have reported in detail how orthopedic surgeons should be protected during surgery in the operating room. No detailed studies on multidisciplinary cooperation, strict protection, protection training, indications of emergency surgery, first aid on-site and protection in orthopedic wards were found. CONCLUSION: Strict protection at every step in the patient pathway is important to reduce the risk of cross-infection. Lessons learnt from our experience provide some recommendations of protective measures during the entire diagnosis and treatment process of traumatic patients and help others to manage orthopedic patients with COVID-19, to reduce the risk of cross-infection between patients and to protect healthcare workers during work. LEVEL OF EVIDENCE: IV.


Subject(s)
Coronavirus Infections/prevention & control , Cross Infection/prevention & control , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Orthopedic Procedures/methods , Orthopedics , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Telemedicine/methods , Air Filters , Betacoronavirus , COVID-19 , COVID-19 Testing , China , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/transmission , Elective Surgical Procedures , Emergencies , Emergency Service, Hospital , First Aid , Fractures, Bone/surgery , Humans , Operating Rooms , Orthopedic Surgeons , Personal Protective Equipment , Pneumonia, Viral/diagnosis , Pneumonia, Viral/transmission , SARS-CoV-2 , Transportation of Patients , Trauma Centers
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