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Accelerating PERx reaction enables covalent nanobodies for potent neutralization of SARS-CoV-2 and variants.
Yu, Bingchen; Li, Shanshan; Tabata, Takako; Wang, Nanxi; Cao, Li; Kumar, G Renuka; Sun, Wei; Liu, Jun; Ott, Melanie; Wang, Lei.
  • Yu B; Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Li S; Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Tabata T; Gladstone Institutes, San Francisco, CA 94158, USA.
  • Wang N; Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Cao L; Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Kumar GR; Gladstone Institutes, San Francisco, CA 94158, USA.
  • Sun W; Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Liu J; Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Ott M; Gladstone Institutes, San Francisco, CA 94158, USA.
  • Wang L; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
Chem ; 8(10): 2766-2783, 2022 Oct 13.
Article in English | MEDLINE | ID: covidwho-1936147
ABSTRACT
The long-lasting COVID-19 pandemic and increasing SARS-CoV-2 variants demand effective drugs for prophylactics and treatment. Protein-based biologics offer high specificity, yet their noncovalent interactions often lead to drug dissociation and incomplete inhibition. Here, we have developed covalent nanobodies capable of binding with SARS-CoV-2 irreversibly via a proximity-enabled reactive therapeutic (PERx) mechanism. A latent bioreactive amino acid (FFY) was designed and genetically encoded into nanobodies to accelerate the PERx reaction rate. Compared with the noncovalent wild-type nanobody, the FFY-incorporated covalent nanobodies neutralized both wild-type SARS-CoV-2 and its Alpha, Delta, Epsilon, Lambda, and Omicron variants with drastically higher potency. This PERx-enabled covalent-nanobody strategy and the related insights into increased potency can be valuable to developing effective therapeutics for various viral infections.
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Full text: Available Collection: International databases Database: MEDLINE Topics: Long Covid / Variants Language: English Journal: Chem Year: 2022 Document Type: Article Affiliation country: J.chempr.2022.07.012

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Full text: Available Collection: International databases Database: MEDLINE Topics: Long Covid / Variants Language: English Journal: Chem Year: 2022 Document Type: Article Affiliation country: J.chempr.2022.07.012