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Updated: Nov 8, 2025
Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
Computational design and modeling of nanobodies toward SARS-CoV-2 receptor binding domain
Jingyi Yang1, Zhao Zhang1, Fengyuan Yang1,2
1School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, China.
Abstract:
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern and pose a serious threat to humanity. There is an urgent need for developing therapeutic drugs and (or) biologics to prevent the spread of the virus. The life cycle of SARS-CoV-2 shows that the virus enters host cells by first binding to angiotensin-converting enzyme 2 (ACE2) through its spike protein receptor-binding domain (RBD). Therefore, blocking the binding between of ACE2 and SARS-CoV-2 RBD can inhibit the virus infection in the host cells. In this study, by grafting the complementarity-determining regions (CDRs) of developed SARS-CoV, MERS-CoVs specific neutralizing antibodies (nAbs) include monoclonal antibodies (mAbs) as well as SARS-CoV-2 mAbs onto a known stable nanobody (Nb) scaffold, and a total of 16 Nbs sequences were designed. Five Nbs, namely CS01, CS02, CS03, CS10, and CS16, were selected based on the free energy landscape of protein docking verified by the recently reported Nb-RBD cocrystal structures. CS01, CS02, and CS03 occupied the ACE2 binding site of RBD, while CS10 and CS16 were proposed to inhibit the interaction between RBD and ACE2 through an allosteric mechanism. Based on the structures of the five Nbs in complex with RBD, seven brand-new Nbs with enhanced binding affinities (CS02_RD01, CS03_RD01, CS03_RD02, CS03_RD03, CS03_RD04, CS16_RD01, and CS16_RD02) were generated by redesign of residues on the interface of the five Nbs contact with SARS-CoV-2 RBD. In addition, the identified "hot spots" on the interface of each complex provide useful information to understand the binding mechanism of designed Nbs to SARS-CoV-2 RBD. In sum, the predicted stabilities and high binding affinities of the 11 (re)designed Nbs indicating the potential of the developed computational framework in this work to design effective agents to block the infection of SARS-CoV-2.
Insights
Researchers designed novel nanobodies (Nbs) to block SARS-CoV-2 infection by targeting the spike protein. These Nbs show high binding affinity and stability, offering potential therapeutic agents against COVID-19.
Area of Science:
- Biochemistry
- Structural Biology
- Immunology
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates new therapeutic strategies.
- SARS-CoV-2 infects host cells by binding ACE2 via its spike protein receptor-binding domain (RBD).
- Inhibiting the RBD-ACE2 interaction is a key strategy to prevent viral entry.
Purpose of the Study:
- To design and develop novel nanobodies (Nbs) capable of blocking SARS-CoV-2 entry into host cells.
- To engineer Nbs with enhanced binding affinities and stabilities against the SARS-CoV-2 RBD.
Main Methods:
- Grafting complementarity-determining regions (CDRs) from neutralizing antibodies onto a nanobody scaffold.
- Computational protein design and docking simulations to select and optimize Nb candidates.
- Structural analysis of Nb-RBD complexes to understand binding mechanisms.
Main Results:
- Designed 16 Nbs, selecting 5 (CS01, CS02, CS03, CS10, CS16) based on binding energy and structural data.
- Identified distinct binding mechanisms: direct ACE2 site blocking (CS01, CS02, CS03) and allosteric inhibition (CS10, CS16).
- Generated 7 enhanced Nbs with improved binding affinities through interface residue redesign.
Conclusions:
- The developed computational framework successfully designed stable Nbs with high binding affinities to SARS-CoV-2 RBD.
- The 11 designed and redesigned Nbs show potential as therapeutic agents to inhibit SARS-CoV-2 infection.
- Understanding binding "hot spots" aids in designing effective antiviral agents.
