Shark bridge beta for windows4/10/2023 Since shark blood and body fluids contain high concentration of urea (about 350 × 10 −3 m), shark-derived vnarbodies may possess better physiochemical stability than human-derived antibodies. We took a different approach by searching shark-derived single domain antibodies, VNAR, which we termed it as vnarbodies to distinguish from camel-derived nanobodies, for neutralizing SARS-CoV-2. One of the advantages of single-domain antibodies is that they can bind to epitopes that are not reachable by traditional human antibodies because of their smaller size and structure.Ī few camelid-derived nanobodies against the RBD region of the SARS-CoV-2 Spike (S) protein have been reported recently. Single-domain antibodies have advantages such as high affinity to target proteins, better thermal stability, small molecular weight, and low production cost in nonmammalian expression systems. Another class of single-domain antibodies, namely variable new antigen receptor (VNAR), having a smaller molecular weight of 13 kD, was found in cartilaginous fish such as sharks, skates, and rays. The first nanobody-based medicine was approved to treat acquired thrombotic thrombocytopenic purpura (aTTP) in 2018. Nanobodies have shown great potential in biomedical applications, including cancer, infection, autoimmune disease, inflammation, and other diseases. Single-domain antibodies or variable domain of the heavy chain of HACbs (VHH) from camelids, having a smaller molecular weight (15 kD) than human antibodies (150 kD), are commonly termed nanobodies. However, the high production costs, large doses needed, and low-temperature requirements for transportation and storage make it challenging to apply on a large scale cost-effectively. Many human-derived SARS-CoV-2 neutralizing antibodies targeting S protein have been identified and developed, some of which have entered clinical trials. S2 is responsible for fusing the virus with cellular membranes. S1 binds the host cell receptor angiotensin-converting enzyme 2 (ACE2) by the receptor-binding domain (RBD), which serves as the primary target for neutralizing antibodies. The spike is composed of two subunits, S1 and S2. Like other coronaviruses, SARS-CoV-2 entry into host cells is mediated by the homotrimeric spike (S) glycoprotein. The convalescent serum has been used to treat COVID-19 patients with a considerable effect but is limited by the scarcity of sources and possible side effects. In this case, the role of passive immunity is significant. The vaccine's protective effect is greatly reduced in people with weakened immune systems, such as elderly and people with immune-compromised conditions. In addition to the active immunity brought by vaccination, the passive immunity of neutralizing antibodies can play an important role in preventing and treating infectious diseases. Understanding mechanisms of virus neutralization and the escape will expedite our effort in virus prevention and therapy. Effective and affordable preventive and therapeutic strategies are urgently needed. These variants brought considerable challenges to the prevention and treatment of SARS-CoV-2 infections. Many SARS-CoV-2 variants appeared under selective pressure from host immunity with high infectivity and immune evasion, such as the Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Gamma (P.1) and Omicron (B.1.1.529). Since the outbreak of the COVID-19 pandemic in December 2019, about 5 billion people have been infected and more than 6 million deaths have been reported to World Health Organization as of April 9, 2022. The study demonstrates that shark-derived vnarbodies offer a prophylactic and therapeutic option against most SARS-CoV-2 variants and provide insights into antibody evasion by the Omicron variant. It is found that the S375F mutation on Omicron RBD disrupts the structure of β-strand, thus impair the binding with 20G6. 20G6 and 17F6 contain a unique “WXGY” motif in the complementary determining region 3 that binds to a hidden epitope on RBD, which is highly conserved in sarbecoviruses through a novel β-sheet interaction. Intranasal administration of 20G6 effectively protects mice from the challenges of SARS-CoV-2 Wuhan and Beta variants. Vnarbody 20G6 and 17F6 have broad neutralizing activities against all these SARS-CoV-2 viruses as well as other sarbecoviruses, including Pangolin coronavirus and Bat coronavirus. The identification of a novel class of shark-derived single domain antibodies, named vnarbodies that show picomolar affinities binding to the receptor binding domain (RBD) of Wuhan and Alpha, Beta, Kappa, Delta, Delta-plus, and Lambda variants, is reported.
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