Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease

A major outbreak of asthma associated with a thunderstorm: Experience of accident and emergency departments and patients' characteristics

Objective - To investigate the time course of an epidemic of asthma after a thunderstorm, characteristics of patients affected, and the demand on emergency medical resources. Design - Study of registers and records in accident and emergency departments and questionnaire to staff Setting - London area. Subjects - All patients presenting at 12 accident and emergency departments with asthma or other airways disease. Main outcome measures-Numbers of patients, clinical features, information on shortage of resources-equipment, drugs, and staff. Results - The epidemic had a sudden onset on 24 June 1994; 640 patients with asthma or other airways disease attended during 30 hours from 1800 on 24 June, nearly 10 times the expected number. Over half (365) the patients were aged 21 to 30 years. A history of hay fever was recorded in 403 patients; for 283 patients this was the first known attack of asthma; a history of chronic obstructive airways disease was recorded in 12 patients. In all, 104 patients were admitted (including five to an intensive care unit). Several departments ran out of equipment or drugs, caned in additional doctors, or both. Concusions - This study supports the view that this epidemic was larger than previously reported epidemics and the hypothesis that 'thunderstorm associated asthma' is related to aeroallergens. Demands on resources were considerable; a larger proportion of patients needing intensive care would have caused greater problems

A major outbreak of asthma associated with a thunderstorm: Experience of accident and emergency departments and patients' characteristics

Objective - To investigate the time course of an epidemic of asthma after a thunderstorm, characteristics of patients affected, and the demand on emergency medical resources. Design - Study of registers and records in accident and emergency departments and questionnaire to staff Setting - London area. Subjects - All patients presenting at 12 accident and emergency departments with asthma or other airways disease. Main outcome measures-Numbers of patients, clinical features, information on shortage of resources-equipment, drugs, and staff. Results - The epidemic had a sudden onset on 24 June 1994; 640 patients with asthma or other airways disease attended during 30 hours from 1800 on 24 June, nearly 10 times the expected number. Over half (365) the patients were aged 21 to 30 years. A history of hay fever was recorded in 403 patients; for 283 patients this was the first known attack of asthma; a history of chronic obstructive airways disease was recorded in 12 patients. In all, 104 patients were admitted (including five to an intensive care unit). Several departments ran out of equipment or drugs, caned in additional doctors, or both. Concusions - This study supports the view that this epidemic was larger than previously reported epidemics and the hypothesis that 'thunderstorm associated asthma' is related to aeroallergens. Demands on resources were considerable; a larger proportion of patients needing intensive care would have caused greater problems