7X4I

Crystal structure of nanobody aSA3 in complex with dimer SARS-CoV-1 RBD

Summary for 7X4I

• Entry DOI: 10.2210/pdb7x4i/pdb
• Descriptor: Spike glycoprotein, nanobody aSA3 (2 entities in total)
• Functional Keywords: nanobody, sars-cov-1, rbd, antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus; More
• Total number of polymer chains: 8
• Total formula weight: 145554.56

Authors

Ma, H.,Zeng, W.H.,Jin, T.C. (deposition date: 2022-03-02, release date: 2023-01-11, Last modification date: 2023-11-29)

Primary citation

Ma, H.,Zhang, X.,Zeng, W.,Zhou, J.,Chi, X.,Chen, S.,Zheng, P.,Wang, M.,Wu, Y.,Zhao, D.,Gong, F.,Lin, H.,Sun, H.,Yu, C.,Shi, Z.,Hu, X.,Zhang, H.,Jin, T.,Chiu, S.
A bispecific nanobody dimer broadly neutralizes SARS-CoV-1 & 2 variants of concern and offers substantial protection against Omicron via low-dose intranasal administration.
Cell Discov, 8:132-132, 2022

PubMed Abstract: Current SARS-CoV-2 Omicron subvariants impose a heavy burden on global health systems by evading immunity from most developed neutralizing antibodies and vaccines. Here, we identified a nanobody (aSA3) that strongly cross-reacts with the receptor binding domain (RBD) of both SARS-CoV-1 and wild-type (WT) SARS-CoV-2. The dimeric construct of aSA3 (aSA3-Fc) tightly binds and potently neutralizes both SARS-CoV-1 and WT SARS-CoV-2. Based on X-ray crystallography, we engineered a bispecific nanobody dimer (2-3-Fc) by fusing aSA3-Fc to aRBD-2, a previously identified broad-spectrum nanobody targeting an RBD epitope distinct from aSA3. 2-3-Fc exhibits single-digit ng/mL neutralizing potency against all major variants of concerns including BA.5. In hamsters, a single systemic dose of 2-3-Fc at 10 mg/kg conferred substantial efficacy against Omicron infection. More importantly, even at three low doses of 0.5 mg/kg, 2-3-Fc prophylactically administered through the intranasal route drastically reduced viral RNA loads and completely eliminated infectious Omicron particles in the trachea and lungs. Finally, we discovered that 2(Y29G)-3-Fc containing a Y29G substitution in aRBD-2 showed better activity than 2-3-Fc in neutralizing BA.2.75, a recent Omicron subvariant that emerged in India. This study expands the arsenal against SARS-CoV-1, provides potential therapeutic and prophylactic candidates that fully cover major SARS-CoV-2 variants, and may offer a simple preventive approach against Omicron and its subvariants.

PubMed: 36494344
DOI: 10.1038/s41421-022-00497-w

Experimental method

X-RAY DIFFRACTION (3.38 Å)