10 oktober 2020: Bron: Kennislink

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Met computer ontworpen eiwit blokkeert coronavirus

Auteur:  | 7 oktober 2020

Amerikaanse wetenschappers hebben met de computer een kunstmatig eiwit ontworpen dat het coronavirus blokkeert in de luchtwegen. Dit mini-eiwit is zo klein dat het verwerkt kan worden in een neusspray en inhalator.

Als het aan een team Amerikaanse wetenschappers ligt, kunnen de mondkapjes over een tijdje de prullenbak in en kunnen we met een gerust hart afspreken met vrienden en familie. Het enige wat we dan nodig hebben is een neusspray en inhalator. Even een snuif in ieder neusgat en een flinke puf van de inhalator en we zijn tijdelijk beschermd tegen het virus.

Spijkereiwitten blokkeren

In die neusspray en inhalator zit dan een klein eiwit dat SARS-CoV-2 neutraliseert. Dat eiwit ontwierpen de wetenschappers met de computer. Een programma berekende precies hoe zo’n mini-eiwit eruit moet zien om het virus te binden en onschadelijk te maken.

Het doelwit van de mini-eiwitten zijn de spijkervormige uitsteeksels op het oppervlakte van het coronavirus. Met die spijkereiwitten haakt het virus zich vast aan menselijke cellen, waarna het zijn genetisch materiaal de cel instuurt. Het mini-eiwit dekt de kenmerkende spijkereiwitten af, en voorkomt daarmee dat het virus cellen infecteert. De onderzoekers publiceerden hun resultaten in het wetenschappelijk tijdschrift Science.

De mini-eiwitten blokkeren het virus op een vergelijkbare manier als antistoffen tegen SARS-CoV-2. Antistoffen zijn onderdeel van het immuunsysteem en komen van nature voor in ons lichaam. “Een voordeel van de nieuwe mini-eiwitten ten opzichte van antistoffen is dat ze sneller, eenvoudiger en goedkoper te maken zijn”, aldus de auteurs.>>>>>>>lees verder

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Science  09 Sep 2020:
eabd9909
DOI: 10.1126/science.abd9909

Abstract

Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0.16 ng/ml). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.

SARS-CoV-2 infection generally begins in the nasal cavity, with virus replicating there for several days before spreading to the lower respiratory tract (1). Delivery of a high concentration of a viral inhibitor into the nose and into the respiratory system generally might therefore provide prophylactic protection and/or therapeutic benefit for treatment of early infection, and could be particularly useful for healthcare workers and others coming into frequent contact with infected individuals. A number of monoclonal antibodies are in development as systemic treatments for COVID-19 (26), but these proteins are not ideal for intranasal delivery as antibodies are large and often not extremely stable molecules and the density of binding sites is low (two per 150 KDa. antibody); antibody-dependent disease enhancement (79) is also a potential issue. High-affinity Spike protein binders that block the interaction with the human cellular receptor angiotensin-converting enzyme 2 (ACE2) (10) with enhanced stability and smaller sizes to maximize the density of inhibitory domains could have advantages over antibodies for direct delivery into the respiratory system through intranasal administration, nebulization or dry powder aerosol. We found previously that intranasal delivery of small proteins designed to bind tightly to the influenza hemagglutinin can provide both prophylactic and therapeutic protection in rodent models of lethal influenza infection (11).

References and Notes

Acknowledgments: We thank Samer Halabiya for MiSeq support, Erik Procko for Fc tagged RBD protein, Kandise Van Wormer and Austin Curtis Smith for their tremendous laboratory support during COVID-19. Funding: This work was supported by DARPA Synergistic Discovery and Design (SD2) HR0011835403 contract FA8750-17-C-0219 (L.C., B.C., D.B.), The Audacious Project at the Institute for Protein Design (L.K., L.C.), funding from Eric and Wendy Schmidt by recommendation of the Schmidt Futures program (L.M.,I.G.) the Open Philanthropy Project Improving Protein Design Fund (B.C.,D.B.), an Azure computing resource gift for COVID-19 research provided by Microsoft (L.C.,B.C.), the National Institute of General Medical Sciences (R01GM120553 to D.V.), the National Institute of Allergy and Infectious Diseases (HHSN272201700059C, D.V., D.B., L.S.), a Helen Hay Whitney Foundation postdoctoral fellowship (J.B.C.), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (D.V.), a Fast Grant award (D.V.) and the University of Washington Arnold and Mabel Beckman cryo-EM center. Author contribution: L.Cao and D.B. designed the research; L.Cao developed the computational methods for Approach I and made the designs based on the ACE2 helix; L.Cao and B.C. developed the computational methods for Approach II and L.Cao made the de novo designs; B.C., L.Cao and E.M.S. designed the de novo scaffold library; L.Cao, I.G. and L.K. performed the yeast display assays and next generation sequencing; L.Cao, I.G., L.M., L.K., A.C.W. and L. Carter purified and prepared the proteins; L.Cao, I.G. and L.M. performed the BLI assays; L.Cao and L.M. collected the circular dichroism results; Y.P. and D.V. solved the CryoEM structures; J.B.C. and R.E.C. performed the SARS-CoV-2 neutralization assay; L.S., M.S.D., D.V. and D.B. supervised the research; L.Cao, J.B.C., Y.P., L.S., D.V. and D.B wrote the manuscript; all authors discussed the results and commented on the manuscript. Competing interests: L.Cao, I.G., B.C., L.M., L.K., and D.B. are co-inventors on a provisional patent application that incorporates discoveries described in this manuscript. D.B. is a cofounder of Neoleukin Therapeutics. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and on the Scientific Advisory Board of Moderna. D.V. has a sponsored research agreement from Vir Biotechnology Inc. Data and materials availability:The design models and design scripts used in the manuscript have been deposited to http://files.ipd.uw.edu/pub/SARS-CoV-2_binder_2020/scripts_models.zip. The cryo-EM maps and atomic models have been deposited at the Electron Microscopy Data Bank and the PDB with accession codes EMD: 22532 and PDB: 7JZL (SARS-CoV-2 S/LCB1), EMD: 22574 and PDB: 7JZU (SARS-CoV-2 S/LCB1, local refinement), EMD: 22534 (SARS-CoV-2 S/LCB3, 2 RBDs open), EMD: 22533 and PDB: 7JZM (SARS-CoV-2 S/LCB3, local refinement), EMD: 22535 (SARS-CoV-2 S/LCB3, 3 RBDs open). This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.
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