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Structure ; 30(5): 707-720.e5, 2022 05 05.
Article in English | MEDLINE | ID: covidwho-1829569


Because of the evolutionary variants of SARS-CoV-2, development of broad-spectrum neutralizing antibodies resilient to virus escape is urgently needed. We identified a group of high-affinity nanobodies from camels immunized with receptor-binding domain (RBD) of SARS-CoV-2 spike protein and resolved the structures of two non-competing nanobodies (NB1A7 and NB1B11) in complex with RBD using X-ray crystallography. The structures show that NB1A7 targets the highly conserved cryptic epitope shared by SARS-CoV-2 variants and some other coronaviruses and blocks ACE2 receptor attachment of the spike protein, and NB1B11 epitope overlaps with the contacting surface of ACE2 and is different from the binding site of NB1A7. These two nanobodies were covalently linked into multivalent and bi-paratopic formats, which significantly improved the avidity and neutralization potency and may further inhibit viral escape. The results contribute to the structure-guided design of antibodies against future variants of SARS-CoV-2 virus to combat coronavirus epidemics and pandemics.

COVID-19 , Single-Domain Antibodies , Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing , Broadly Neutralizing Antibodies , Epitopes/metabolism , Humans , Protein Binding , SARS-CoV-2/genetics , Single-Domain Antibodies/chemistry , Single-Domain Antibodies/genetics , Spike Glycoprotein, Coronavirus/chemistry
Proc Natl Acad Sci U S A ; 119(15): e2120913119, 2022 04 12.
Article in English | MEDLINE | ID: covidwho-1758464


SignificanceThe coronavirus main protease (Mpro) is required for viral replication. Here, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro by trapping it with nanobodies and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. Another monomeric state is termed compact conformation and is similar to one protomer of the dimeric form. We designed a Nanoluc Binary Techonology (NanoBiT)-based high-throughput allosteric inhibitor assay based on structural conformational change. Our results provide insight into the maturation, dimerization, and catalysis of the coronavirus Mpro and pave a way to develop an anticoronaviral drug through targeting the maturation process to inhibit the autocleavage of Mpro.

Antiviral Agents , COVID-19 , Coronavirus 3C Proteases , Protease Inhibitors , SARS-CoV-2 , Allosteric Regulation/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/enzymology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Humans , Luciferases , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Conformation , Protein Multimerization
Am J Trop Med Hyg ; 105(2): 368-371, 2021 Jun 15.
Article in English | MEDLINE | ID: covidwho-1270182


Sickle cell trait (SCT) carriers inherit one copy of the Glu6Val mutation in the hemoglobin gene and is particularly common in Black individuals (5-10%). Considering the roles of hemoglobin in immune responses and the higher risk for coronavirus disease (COVID-19) among Black individuals, we tested whether Black SCT carriers were at increased risk for COVID-19 infection and mortality according to the United Kingdom Biobank. Among Black individuals who were tested for COVID-19, we found similar infection rates among SCT carriers (14/72; 19.7%) and noncarriers (167/791; 21.1%), but higher COVID-19 mortality rates among SCT carriers (4/14; 28.6%) than among noncarriers (21/167; 12.6%) (odds ratio [OR], 3.04; 95% confidence interval [CI], 0.69-11.82; P = 0.12). Notably, SCT carriers with preexisting diabetes had significantly higher COVID-19 mortality (4/4; 100%) than those without diabetes (0/10; 0%; (OR, 90.71; 95% CI, 5.66-infinite; P = 0.0005). These findings suggest that Black SCT carriers with preexisting diabetes are at disproportionally higher risk for COVID-19 mortality. Confirmation by larger studies is warranted.

Biological Specimen Banks/statistics & numerical data , COVID-19/mortality , Sickle Cell Trait/complications , Adult , Aged , COVID-19/epidemiology , COVID-19/ethnology , Diabetes Complications/epidemiology , Female , Humans , Male , Middle Aged , Odds Ratio , Population , Preexisting Condition Coverage/statistics & numerical data , Risk Factors , Sickle Cell Trait/epidemiology , Sickle Cell Trait/ethnology , United Kingdom