Trivalent Antiviral Conjugates Trap Influenza Viruses by Cross-Linking Them Together

Influenza remains one of the most stubborn viral threats to global health, and the antiviral arsenal available to clinicians is still surprisingly thin. A new study published in Nature Communications reports a design strategy that could broaden that arsenal considerably. A team led by researchers at the Academy of Military Medical Sciences in Beijing, working with collaborators at Tsinghua University, Xiamen University and the University of Hong Kong, has developed a programmable platform for building multivalent antiviral conjugates, or AVCs, in which several copies of an approved antiviral drug are chemically tethered to an antibody-derived Fc fragment. The work shows that simply increasing the number of drug molecules attached to a single Fc scaffold does more than raise potency: it fundamentally changes how the drug fights the virus.

The starting point for the study was CD388, a long-acting drug–Fc conjugate that has recently emerged as a new class of antiviral against both influenza A and influenza B. CD388 links a small-molecule inhibitor to the crystallizable fragment of an antibody, extending the drug’s residence time in the body while retaining its ability to bind the viral target. What remained unclear, however, was how exactly the Fc conjugation reshapes the function of the small molecule it carries. The researchers set out to answer that question systematically, and in doing so they uncovered a mechanism that had not been appreciated before.

To do this, the team built a platform based on click chemistry, a family of highly reliable bioconjugation reactions that allow molecular building blocks to be joined in a modular, almost Lego-like fashion. The platform makes it possible to flexibly combine different valencies, meaning different numbers of drug copies, with different conjugated drugs on the same Fc scaffold. Using the neuraminidase inhibitor zanamivir as a model drug, the researchers prepared mono-, di- and trivalent versions, each carrying one, two or three zanamivir molecules attached to the Fc fragment. This controlled series allowed them to interrogate, for the first time in a rigorous way, how valency alone governs antiviral behavior.

The results were striking. The trivalent zanamivir–Fc conjugate, designated AVC-Z3, exhibited higher antiviral activity than the mono- and divalent versions. But the more important discovery was mechanistic. Rather than merely blocking the enzymatic activity of viral neuraminidase more strongly, AVC-Z3 did something physically dramatic: it induced inter-virion aggregation. Because each conjugate carries three zanamivir ligands, a single AVC-Z3 molecule can bind neuraminidase proteins on more than one virus particle at the same time, cross-linking the virions into aggregates. The Fc fragment, with its own multivalent binding capacity, further supports this clustering effect.

This cross-linking produces a dual-stage inhibition that represents a genuine mechanistic shift. In the traditional view, neuraminidase inhibitors such as zanamivir and oseltamivir work by suppressing the enzyme that influenza uses to cleave sialic acid receptors, a step essential for newly formed virions to detach from an infected cell and spread. With AVC-Z3, the blockade of viral entry is coupled to the restriction of viral release. Virions that are cross-linked into aggregates cannot move freely, attach efficiently to new cells, or escape from the surfaces where they are produced. In effect, the drug no longer just disables a viral enzyme; it physically immobilizes the virus particles themselves.

The implications of this shift are considerable. A mechanism based on physical cross-linking is less dependent on the precise chemistry of the neuraminidase active site, which is where most resistance mutations to conventional inhibitors arise. By converting a single-target enzyme inhibitor into a multivalent cross-linking agent, the platform could in principle make it harder for the virus to escape through the usual mutational routes. The authors describe ligand valency as a determinant of antiviral mechanism, a framing that elevates valency from a simple potency knob to a design parameter that controls what kind of antiviral activity a conjugate delivers.

Encouraged by the zanamivir results, the team applied the same logic to a second neuraminidase inhibitor, peramivir. They synthesized a trivalent peramivir–Fc conjugate, AVC-P3, and found that it showed stronger antiviral activity than AVC-Z3 in vitro. Just as importantly, AVC-P3 displayed a much longer half-life in vivo than AVC-Z3 and than CD388 carrying the YTE mutation, an Fc engineering change often used to extend antibody half-life by improving binding to the neonatal Fc receptor. The combination of high potency and long persistence is exactly what is wanted in a long-acting prophylactic or therapeutic agent, particularly for vulnerable populations or outbreak settings where dosing logistics are difficult.

The in vivo performance of AVC-P3 was tested in mouse models of infection with four different influenza challenges: H1N1, H3N2, H5N1 and influenza B. Across all of these models, the efficacy of AVC-P3 surpassed that of the other AVCs, of baloxavir, a cap-dependent endonuclease inhibitor that represents one of the newest classes of influenza drugs, and of CD388 itself. Covering both influenza A subtypes, including the highly pathogenic H5N1, and influenza B in a single agent speaks to the breadth that the neuraminidase-targeting, Fc-conjugated approach can offer. H5N1 remains a pandemic concern given its ongoing circulation in birds and sporadic human infections, so a long-acting agent active against it has obvious strategic value.

The study also carries a broader message for antiviral drug design. Small-molecule antivirals and biologics have traditionally occupied separate worlds, with small molecules prized for potency and manufacturability and antibodies valued for specificity and long half-life. Drug–Fc conjugates blur that boundary, and the present work demonstrates that the design space within that hybrid class is richer than assumed. By making valency programmable, the click-chemistry platform turns the number of drug copies per Fc into an experimentally tunable variable, allowing researchers to map how valency reshapes mechanism, potency and pharmacokinetics. The finding that trivalency unlocks cross-linking suggests that other viral targets with dense surface display of ligands, such as hemagglutinin or surface glycoproteins of unrelated viruses, might be amenable to the same strategy.

Caveats remain, as they always do at this stage. The efficacy data come from mouse models, and the pharmacokinetic advantages observed in animals will need to be confirmed in higher species before the approach can be considered for clinical development. Questions about manufacturing consistency, immunogenicity of the conjugates and the behavior of virion aggregates in the complex environment of the human respiratory tract will all require attention. Nevertheless, the study defines a clear principle: ligand valency is not merely a matter of avidity but a switch that can convert a conventional enzyme inhibitor into a physically immobilizing, dual-stage antiviral. If that principle holds up through further development, the multivalent conjugate platform could offer a durable new line of defense against a virus that has repeatedly shown its capacity to surprise.

Subject of Research: Multivalent drug–Fc conjugates that cross-link influenza virions to enhance antiviral activity

Article Title: Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses

Article References: Feng, X., Yuan, L., Zhao, L., Liu, L., Xie, F., Zhou, M., Cheng, G., Guan, Y., Xia, N., Cheng, T., Zhong, W., Xiao, D., Zhou, X., & Li, S. (2026). Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses. Nature Communications. https://doi.org/10.1038/s41467-026-78126-3

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78126-3

Keywords: influenza, antivirals, drug–Fc conjugates, multivalency, neuraminidase inhibitors, zanamivir, peramivir, CD388, cross-linking, viral aggregation, H5N1, drug development