Functional and antigenic constraints on the Nipah virus fusion protein Article Swipe
Brendan B. Larsen
,
Sheri Harari
,
Risako Gen
,
Cameron Stewart
,
David Veesler
,
Jesse D. Bloom
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.10.15.682664
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.10.15.682664
Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use non-replicative pseudoviruses to safely measure the effects of all F single amino-acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus. Importance Nipah virus sporadically spills over into humans, where it is often fatal. The Nipah fusion (F) protein is necessary for infection, and is a target for vaccines and antibody therapies. To better understand the constraints on this protein, we experimentally measured how ∼8,500 single amino-acid mutations to F affected its function using pseudoviruses that enable the safe study of protein mutants without the generation of actual replicative virus. We examined the effects of these mutations in the context of structural data and publicly available Nipah virus sequences to characterize the constraints that shape protein evolution. We make our data publicly available in interactive form at https://dms-vep.org/Nipah_Malaysia_F_DMS/ for additional exploration. This work has implications for understanding paramyxovirus fusion proteins, and informs the development of vaccines and monoclonal antibody therapies.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.10.15.682664
- https://www.biorxiv.org/content/biorxiv/early/2025/10/15/2025.10.15.682664.full.pdf
- OA Status
- green
- References
- 82
- OpenAlex ID
- https://openalex.org/W4415321646
All OpenAlex metadata
Raw OpenAlex JSON
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https://openalex.org/W4415321646Canonical identifier for this work in OpenAlex
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https://doi.org/10.1101/2025.10.15.682664Digital Object Identifier
- Title
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Functional and antigenic constraints on the Nipah virus fusion proteinWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
-
2025-10-15Full publication date if available
- Authors
-
Brendan B. Larsen, Sheri Harari, Risako Gen, Cameron Stewart, David Veesler, Jesse D. BloomList of authors in order
- Landing page
-
https://doi.org/10.1101/2025.10.15.682664Publisher landing page
- PDF URL
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https://www.biorxiv.org/content/biorxiv/early/2025/10/15/2025.10.15.682664.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://www.biorxiv.org/content/biorxiv/early/2025/10/15/2025.10.15.682664.full.pdfDirect OA link when available
- Cited by
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0Total citation count in OpenAlex
- References (count)
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82Number of works referenced by this work
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| referenced_works | https://openalex.org/W2127949919, https://openalex.org/W2147823402, https://openalex.org/W2046310918, https://openalex.org/W1973647109, https://openalex.org/W2943881668, https://openalex.org/W2088173462, https://openalex.org/W2042533947, https://openalex.org/W2003919149, https://openalex.org/W2002155391, https://openalex.org/W1994723404, https://openalex.org/W1869300308, https://openalex.org/W2164027317, https://openalex.org/W1999267207, https://openalex.org/W2021540849, https://openalex.org/W1993703438, https://openalex.org/W2156309934, https://openalex.org/W1982448468, https://openalex.org/W4318578157, https://openalex.org/W4220869301, https://openalex.org/W4394597800, https://openalex.org/W2138584068, https://openalex.org/W2161492108, https://openalex.org/W2199400566, https://openalex.org/W2194722774, https://openalex.org/W4320032928, https://openalex.org/W1570073947, https://openalex.org/W2007459104, https://openalex.org/W3034886260, https://openalex.org/W2089529473, https://openalex.org/W4393864980, https://openalex.org/W2993993873, https://openalex.org/W3157530174, https://openalex.org/W2975454690, https://openalex.org/W3104722250, https://openalex.org/W4320491837, https://openalex.org/W4411187501, https://openalex.org/W3043042882, https://openalex.org/W2063539859, https://openalex.org/W4320497972, https://openalex.org/W4408789657, https://openalex.org/W2137664170, https://openalex.org/W2070921793, https://openalex.org/W4321787460, https://openalex.org/W4387033201, https://openalex.org/W4400680285, https://openalex.org/W2790509526, https://openalex.org/W1644209505, https://openalex.org/W1978118805, https://openalex.org/W2895239334, https://openalex.org/W2901117869, https://openalex.org/W1976011619, https://openalex.org/W2076898581, https://openalex.org/W1965662372, https://openalex.org/W2003829444, https://openalex.org/W4405988258, https://openalex.org/W4400079021, https://openalex.org/W4308771634, https://openalex.org/W2964965456, https://openalex.org/W4390791894, https://openalex.org/W4327742237, https://openalex.org/W2126114330, https://openalex.org/W4404294209, https://openalex.org/W3003399029, https://openalex.org/W4409668938, https://openalex.org/W2796780818, https://openalex.org/W2872588368, https://openalex.org/W2270213832, https://openalex.org/W2971051863, https://openalex.org/W2126241449, https://openalex.org/W601813356, https://openalex.org/W4317369991, https://openalex.org/W4309469480, https://openalex.org/W2783736669, https://openalex.org/W2990251218, https://openalex.org/W4385479203, https://openalex.org/W4311417717, https://openalex.org/W2160378127, https://openalex.org/W3005235420, https://openalex.org/W4387164156, https://openalex.org/W3177828909, https://openalex.org/W4281790889, https://openalex.org/W4232290140 |
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