Hetero-bivalent nanobodies provide broad-spectrum protection against SARS-CoV-2 variants of concern including Omicron DOI Creative Commons
Huan Ma,

Xinghai Zhang,

Peiyi Zheng

et al.

Cell Research, Journal Year: 2022, Volume and Issue: 32(9), P. 831 - 842

Published: July 29, 2022

SARS-CoV-2 variants with adaptive mutations have continued to emerge, causing fresh waves of infection even amongst vaccinated population. The development broad-spectrum antivirals is thus urgently needed. We previously developed two hetero-bivalent nanobodies (Nbs), aRBD-2-5 and aRBD-2-7, potent neutralization activity against the wild-type (WT) Wuhan isolated SARS-CoV-2, by fusing aRBD-2 aRBD-5 aRBD-7, respectively. Here, we resolved crystal structures these Nbs in complex receptor-binding domain (RBD) spike protein, found that contacts highly-conserved RBD residues retains binding Alpha, Beta, Gamma, Delta, Delta plus, Kappa, Lambda, Omicron BA.1, BA.2 variants. In contrast, aRBD-7 bind less-conserved epitopes non-overlapping epitope aRBD-2, do not show apparent some However, when fused they effectively enhance overall affinity. Consistently, aRBD-2-5-Fc aRBD-2-7-Fc potently neutralized all tested authentic or pseudotyped viruses, including WT, BA.1.1 BA.2. Furthermore, provided prophylactic protection WT mouse-adapted mice, conferred BA.1 variant hamsters prophylactically therapeutically, indicating could potentially benefit prevention treatment COVID-19 caused emerging concern. Our strategy provides new solutions therapeutic antibodies for COVID-19.

Language: Английский

Nanotechnology-based strategies against SARS-CoV-2 variants DOI Open Access
Xiangang Huang, Edo Kon, Xuexiang Han

et al.

Nature Nanotechnology, Journal Year: 2022, Volume and Issue: 17(10), P. 1027 - 1037

Published: Aug. 18, 2022

Language: Английский

Citations

103
Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants DOI Creative Commons
James W. Saville, Dhiraj Mannar, Xing Zhu

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Feb. 8, 2022

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India late 2020, with the variant underlying resurgence COVID-19, even countries high vaccination rates. In this study, we assess structural biochemical aspects viral fitness for these two using cryo-electron microscopy (cryo-EM), ACE2-binding antibody neutralization analyses. Both demonstrate escape antibodies targeting N-terminal domain, an important immune hotspot neutralizing epitopes. Compared to wild-type lineages, spike proteins show modest increase ACE2 affinity, likely due enhanced electrostatic complementarity at RBD-ACE2 interface, which characterize by cryo-EM. Unexpectedly, trimers form a head-to-head dimer-of-trimers assembly, is result E484Q mutation unknown biological implications. combination increased binding provides explanation, part, rapid global dominance variant.

Language: Английский

Citations

96
A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo DOI Creative Commons
Leo Hanke, Hrishikesh Das, Daniel J. Sheward

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 10, 2022

Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show potential for virus escape. This emphasizes need molecules with distinct and novel neutralization mechanisms. Here we describe isolation of a nanobody that interacts simultaneously two RBDs from different trimers SARS-CoV-2, rapidly inducing formation trimer-dimers leading loss their ability attach host cell receptor, ACE2. We this potently neutralizes including beta delta variants, cross-neutralizes SARS-CoV. Furthermore, demonstrate against SARS-CoV-2 variant in human ACE2 transgenic mouse model. naturally elicited bispecific monomeric establishes an uncommon strategy potent inactivation viral antigens represents promising antiviral variants.

Language: Английский

Citations

73
Nanobodies: Robust miniprotein binders in biomedicine DOI Creative Commons

Jeffrey Yong Joon Kim,

Zhe Sang, Yufei Xiang

et al.

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 195, P. 114726 - 114726

Published: Feb. 7, 2023

Language: Английский

Citations

43
Sensitivity to Vaccines, Therapeutic Antibodies, and Viral Entry Inhibitors and Advances To Counter the SARS-CoV-2 Omicron Variant DOI
Hao Zhou, Michelle Møhlenberg,

Jigarji Chaturji Thakor

et al.

Clinical Microbiology Reviews, Journal Year: 2022, Volume and Issue: 35(3)

Published: June 6, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps evolving and mutating into newer variants over time, which gain higher transmissibility, disease severity, spread in communities at a faster rate, resulting multiple waves of surge Coronavirus Disease 2019 (COVID-19) cases. A highly mutated transmissible SARS-CoV-2 Omicron variant has recently emerged, driving the extremely high peak infections almost all continents an unprecedented speed scale. The evades protection rendered by vaccine-induced antibodies natural infection, as well overpowers antibody-based immunotherapies, raising concerns current effectiveness available vaccines monoclonal therapies. This review outlines most recent advancements studying virology biology variant, highlighting its increased resistance to therapeutics immune escape against vaccines. However, is sensitive viral fusion inhibitors targeting HR1 motif spike protein, enzyme inhibitors, involving endosomal pathway, ACE2-based entry inhibitors. variant-associated infectivity mechanisms are essentially distinct from previous characterized variants. Innate sensing evasion T cell immunity virus provide new perspectives vaccine drug development. These findings important for understanding advances developing vaccines, therapies, more effective strategies mitigate transmission or next concern.

Language: Английский

Citations

68
NanoNet: Rapid and accurate end-to-end nanobody modeling by deep learning DOI Creative Commons
Tomer Cohen,

Matan Halfon,

Dina Schneidman‐Duhovny

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 12, 2022

Antibodies are a rapidly growing class of therapeutics. Recently, single domain camelid VHH antibodies, and their recognition nanobody (Nb) appeared as cost-effective highly stable alternative to full-length antibodies. There is need for high-throughput epitope mapping based on accurate structural modeling the variable domains that share common fold differ in Complementarity Determining Regions (CDRs). We develop deep learning end-to-end model, NanoNet, given sequence directly produces 3D coordinates backbone C β atoms entire VH domain. For Nb test set, NanoNet achieves 3.16Å average RMSD most CDR3 loops 2.65Å, 1.73Å CDR1, CDR2 loops, respectively. The accuracy antibody even higher: 2.38Å 0.89Å, 0.96Å run times allow generation ∼1M structures less than 4 hours standard CPU computer enabling structure modeling. available at GitHub: https://github.com/dina-lab3D/NanoNet

Language: Английский

Citations

67
A structural view of the SARS-CoV-2 virus and its assembly DOI Creative Commons
Nathan Hardenbrook, Peijun Zhang

Current Opinion in Virology, Journal Year: 2021, Volume and Issue: 52, P. 123 - 134

Published: Dec. 4, 2021

The SARS-CoV-2 pandemic that struck in 2019 has left the world crippled with hundreds of millions cases and people dead. During this time, we have seen unprecedented support collaboration amongst scientists to respond deadly disease. Advances field structural biology, particular cryoEM cryo-electron tomography, allowed analysis SARS-CoV-2. Here, review work on virus viral components, as well its cellular assembly process, highlighting some important findings made significant impact protection from treatment emerging infections.

Language: Английский

Citations

65
Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants DOI Creative Commons

Jialing Yin,

Chengcheng Li, Chunhong Ye

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 824 - 837

Published: Jan. 1, 2022

Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in late 2019, the coronavirus disease 2019 (COVID-19) pandemic has challenged public health around world. Currently, there is an urgent need to explore antiviral therapeutic targets and effective clinical drugs. In this study, we systematically summarized two main strategies against COVID-19, namely drugs targeting SARS-CoV-2 life cycle SARS-CoV-2-induced inflammation host cells. The development of above implemented by repurposing exploring potential targets. A comprehensive summary promising drugs, especially cytokine inhibitors, traditional Chinese medicine (TCM), provides recommendations for clinicians as evidence-based actual COVID-19 treatment. Considering emerging variants greatly impact effectiveness vaccines, reviewed appearance details further perspectives drug design, which brings updating clues develop therapeutical agents variants. Based on this, broadly combined with immunomodulatory, or holistic therapy host, prior being considered interventions mutant strains SARS-CoV-2. Therefore, it highly acclaimed requirements concerted efforts from multi-disciplinary basic studies trials, improves accurate treatment optimizes contingency measures

Language: Английский

Citations

65
Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape DOI Creative Commons
Fred D. Mast, Peter C. Fridy, Natalia E. Ketaren

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Dec. 7, 2021

The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct highly conserved available epitope space spike, including S1 receptor binding domain, N-terminal S2 subunit, identify sites may reflect novel mechanisms neutralization. Structural mapping functional assays show indeed these stable monovalent nanobodies potently inhibit infection, display numerous neutralization mechanisms, are effective against emerging concern, resistant mutational Rational combinations bind within between spike subunits exhibit extraordinary synergy suggest multiple tailored prophylactic strategies.

Language: Английский

Citations

58
Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment DOI Creative Commons
Jiewen Wang, Guangbo Kang, Haibin Yuan

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 18, 2022

Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative conventional monoclonal also for clinical applications. Furthermore, they do not solely represent substitute but their unique features allow expanding the applications of biotherapeutics and changes pattern disease treatment. Nanobodies possess double advantage being small simple engineer. This combination has promoted extremely diversified approaches design nanobody-based constructs suitable particular Both format geometry possibilities functionalization strategies have been widely explored provide macromolecules with better efficacy respect single or combination. Nanobody multimers nanobody-derived reagents were developed image contrast several cancer diseases shown effectiveness in animal models. Their capacity block more independent signaling pathways simultaneously is considered critical avoid tumor resistance, whereas mass these multimeric compounds still remains significantly smaller than that an IgG, enabling deeper penetration solid tumors. When applied CAR-T cell therapy, can effectively improve specificity by targeting multiple epitopes consequently reduce side effects. represents great potential treating malignant lymphomas, acute myeloid leukemia, lymphoblastic myeloma Apart from treatment, multispecific drugs imaging built nanobody blocks demonstrated value detecting tackling neurodegenerative, autoimmune, metabolic, infectious antidotes toxins. In particular, multi-paratopic recently passive immunization against SARS-CoV-2 goal impairing variant survival due resistance epitopes. Given enormous research activity field, it expected molecules will undergo late trials next future. Systematic Review Registration.

Language: Английский

Citations

56