Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains

Chen, Chuan; Saville, James W.; Marti, Michelle M.; Schäfer, Alexandra; Cheng, Mary Hongying; Mannar, Dhiraj; Zhu, Xing; Berezuk, Alison; Banerjee, Anupam; Sobolewski, Michele D.; Kim, Andrew; Treat, Benjamin R.; Castanha, Priscila M. S.; Enick, Nathan; McCormick, Kevin D.; Liu, Xianglei; Adams, Cynthia R.; Hines, Margaret G; Sun, Zehua; Weizao, Chen,; Jacobs, Jana L.; Barratt‐Boyes, Simon M.; Mellors, John W.; Baric, Ralph S.; Bahar, İvet; Dimitrov, Dimiter S.; Subramaniam, Sriram; Martinez, David R.; Li, Wei

doi:10.1016/j.isci.2022.104798

Cited by 1 publication

(4 citation statements)

References 89 publications

(80 reference statements)

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“…The evaluation of the specificity of engineered Nbs by cross-docking with other viral RBDs/HA showed that all engineered Nbs had a higher binding affinity to their target RBDs than other viral RBDs/ Has. As expected, although all engineered Nb17.1 and Nb23.1 were multi-point mutations, This result indicated that the engineered Nbs could be applied for SARS-CoV-2 broad-specific neutralization [7][8][9]. The finding represents an exciting outcome with a usable yield however, further investigation is required in a biological system to prove their effectiveness in a real environment for the next generation of usability as SARS-CoV-2 prevention, treatment, or diagnosis applications.…”

Section: Broad-specific Evaluation Of Engineered Nbssupporting

confidence: 60%

“…As expected, although all engineered Nb17.1 and Nb23.1 were multi-point mutations, these engineered Nb can bind on the RBM motif as well as the native lead Nbs ( S13 Fig ). This result indicated that the engineered Nbs could be applied for SARS-CoV-2 broad-specific neutralization [ 7 – 9 ]. The finding represents an exciting outcome with a usable yield however, further investigation is required in a biological system to prove their effectiveness in a real environment for the next generation of usability as SARS-CoV-2 prevention, treatment, or diagnosis applications.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, seven engineered Nb17.1 and Nb23.1 (14 new Nbs in total) were obtained, which strongly interacted with their RBD. For example, Nb17.1_A (7), where "Nb17.1" was the original code of lead Nb, "A" was the Alpha variant of RBD, and "( 7)" was the number of mutated residues. The docking score of the engineered Nb17.…”

Section: Plos Onementioning

confidence: 99%

“…Mutations in RBD, particularly in VOCs such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529); BA.1 and BA.2, have been shown to increase virus transmissibility, evade host defenses, and confer the ability to escape immune responses [4][5][6]. As a result, the development of high-specific neutralizing molecules such as nanobodies (Nbs) is critical to combat the emergence of VOCs and their impact on global public health [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Computational design of novel nanobodies targeting the receptor binding domain of variants of concern of SARS-CoV-2

Longsompurana,

Rungrotmongkol,

Plongthongkum

et al. 2023

PLoS ONE

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The COVID-19 pandemic has created an urgent need for effective therapeutic and diagnostic strategies to manage the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the emergence of numerous variants of concern (VOCs) has made it challenging to develop targeted therapies that are broadly specific in neutralizing the virus. In this study, we aimed to develop neutralizing nanobodies (Nbs) using computational techniques that can effectively neutralize the receptor-binding domain (RBD) of SARS-CoV-2 VOCs. We evaluated the performance of different protein-protein docking programs and identified HDOCK as the most suitable program for Nb/RBD docking with high accuracy. Using this approach, we designed 14 novel Nbs with high binding affinity to the VOC RBDs. The Nbs were engineered with mutated amino acids that interacted with key amino acids of the RBDs, resulting in higher binding affinity than human angiotensin-converting enzyme 2 (ACE2) and other viral RBDs or haemagglutinins (HAs). The successful development of these Nbs demonstrates the potential of molecular modeling as a low-cost and time-efficient method for engineering effective Nbs against SARS-CoV-2. The engineered Nbs have the potential to be employed in RBD-neutralizing assays, facilitating the identification of novel treatment, prevention, and diagnostic strategies against SARS-CoV-2.

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Section: Broad-specific Evaluation Of Engineered Nbssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%