Summary
A bioRxiv preprint reports that MERS-CoV spike substitutions L507I and L507H reduced binding to soluble DPP4 while preserving entry into cells with high DPP4 levels. Polymorphisms at the same site found in patient virus sequences showed stronger resistance in the study’s VSV-based cell system.
A bioRxiv preprint reports that several amino-acid changes in the MERS-CoV spike protein can make a laboratory virus less susceptible to soluble DPP4, a molecule being investigated as a decoy antiviral, while preserving efficient entry into cells with abundant DPP4 receptors.
The finding came from laboratory experiments using vesicular stomatitis virus engineered to carry the MERS-CoV spike protein. It describes a potential resistance mechanism under soluble-DPP4 pressure rather than a clinical result.
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What the experiments selected
MERS-CoV uses DPP4, also called CD26, as the receptor that enables the virus to enter cells. Soluble recombinant DPP4 can bind the viral spike protein before the virus reaches a cell, potentially acting as a decoy. Earlier work cited in the preprint had shown that soluble DPP4 could block MERS-CoV infection in cell culture and animal models.
To examine whether the virus could acquire resistance to this blockade, the researchers repeatedly passaged VSV-MERS-S in the presence of soluble DPP4. VSV-MERS-S is a vesicular stomatitis virus carrying the MERS-CoV spike protein, allowing the spike-mediated entry step to be studied in a controlled laboratory system.
The selection produced variants with L507I and L507H substitutions in the receptor-binding domain of spike. These changes reduced binding to soluble DPP4 and conferred resistance to its blocking effect. The substitutions remained compatible with robust entry into cell lines expressing high levels of DPP4.
Why DPP4 abundance mattered
The resistance came with a receptor-density trade-off. Cells expressing low levels of DPP4 showed reduced entry by the variants, whereas cells with high DPP4 levels continued to support robust entry.
This pattern is consistent with a distinction between soluble and cell-surface DPP4. A spike change that weakens interaction with soluble DPP4 can help the virus avoid being intercepted in solution, but efficient entry may still require a sufficiently high concentration of DPP4 on the target cell surface.
The study also examined L507F, L507R and L507P polymorphisms found in MERS-CoV sequences from patients. These variants produced an even more pronounced phenotype. L507R and L507P conferred complete resistance to soluble DPP4 in the reported experiments, while retaining the ability to enter cells with high DPP4 expression.
Implications for soluble-DPP4 antivirals
The results identify a possible evolutionary route around a DPP4-based decoy strategy: changes in the spike receptor-binding domain can reduce soluble-DPP4 binding without eliminating entry under conditions where cells display abundant DPP4.
For antiviral development, the finding highlights the importance of testing both blocking activity and receptor-level requirements. A variant that appears resistant in a soluble-DPP4 assay may still have a disadvantage in tissues or cell types with lower DPP4 abundance. Conversely, environments with high receptor levels could remain permissive to entry by such variants.
The work was posted on bioRxiv on September 20, 2026, as a preprint. Its evidence comes from a VSV-based spike-entry system and cultured cell lines, making it a mechanistic laboratory study of resistance. How the reported substitutions would affect authentic MERS-CoV replication, spread or disease requires further investigation.