S375F mutation in Omicron variants causes destabilization and low production yield of SARS-CoV-2 recombinant Spike proteins.

Matthew Drew, Hannah Ambrose, Zoe Putman, Chao Yan Liu, Sarah Richards, Jonathan Zmuda, Vanessa Wall, Dominic Esposito

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Article in Protein expression and purification, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

8 authors.

Matthew DrewProtein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Hannah AmbroseProtein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Zoe PutmanProtein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Chao Yan LiuThermo Fisher Scientific, Frederick, MD, 21704, USA.

Sarah RichardsThermo Fisher Scientific, Frederick, MD, 21704, USA.

Jonathan ZmudaThermo Fisher Scientific, Frederick, MD, 21704, USA.

Vanessa WallProtein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Dominic EspositoProtein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. Electronic address: desposito@septerna.com.

Funding

Intramural NIH HHS Z99 CA999999

6 · The paper itself

Abstract

Omicron variants of the SARS-CoV-2 Spike protein have been challenging to produce recombinantly at high yields compared to their wild type counterparts. Using a variety of mutants within the receptor-binding domain of Spike, we have been able to identify a specific mutation, S375F, in Omicron variants which leads to the reduced protein production yields, likely due to decreased expression and reduced protein stability. In addition to revertant mutations which can improve the yield of Omicron proteins, we also demonstrate that a new HEK293 expression system, Gibco™ Expi293™ PRO, can restore higher yield for these challenging variants, eliminating the need for additional mutations.

Indexed as

COVID-19Mammalian protein expressionOmicronProtein productionSARS-CoV-2Spike protein

Identifiers

PMID42833500

DOI10.1016/j.pep.2026.107024

PMCPMC13691611

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.