![]() ![]() ![]() In the all-down conformation, the RBDs are packed with their long axes contained in a plane perpendicular to the axis of symmetry of the trimer. The SARS-CoV-2 spike is a trimer of S1/S2 heterodimers with three ACE2 receptor-binding domains (RBDs) attached to the distal end of the spike via a hinge region that allows conformational flexibility ( 4). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of COVID-19 ( 1, 2) that enters human cells by binding its envelope anchored type I fusion protein (spike) to angiotensin-converting enzyme 2 (ACE2) ( 3, 4). The dromedary camel V HH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. ![]() We isolated two V HH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Here, we built large dromedary camel V HH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. Dromedary camels ( Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). ![]()
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