Heteromultivalent topology-matched nanostructures as potent and broad-spectrum influenza A virus inhibitors

Abstract

Here, we report the topology-matched design of heteromultivalent nanostructures as potent and broad-spectrum virus entry inhibitors based on the host cell membrane. Initially, we investigate the virus binding dynamics to validate the better binding performance of the heteromultivalent moieties as compared to homomultivalent ones. The heteromultivalent binding moieties are transferred to nanostructures with a bowl-like shape matching the viral spherical surface. Unlike the conventional homomultivalent inhibitors, the heteromultivalent ones exhibit a half maximal inhibitory concentration of 32.4 ± 13.7 μg/ml due to the synergistic multivalent effects and the topology-matched shape. At a dose without causing cellular toxicity, >99.99% reduction of virus propagation has been achieved. Since multiple binding sites have also been identified on the S protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), we envision that the use of heteromultivalent nanostructures may also be applied to develop a potent inhibitor to prevent coronavirus infection.

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“…The virus propagation was reduced by more than 99.99% at a dose that did not cause cytotoxicity. Since multiple binding sites have also been identified on the S protein of SARS-CoV-2, it is envisaged that heteromultivalent nanostructures may also be employed in seeking effective SARS-CoV-2 inhibitors [ 31 ].…”

“… ( A ) Proposed binding patterns between nano-inhibitor and IAV particles [ 29 ]; ( B ) proposed binding patterns between spiky nanoparticle-based inhibitor and IAV particles [ 30 ]; ( C ) proposed binding patterns between IAV and the heteromultivalent nanobowl (Hetero-MNB), where sialic acid and zanamivir bind to HA and NA, respectively, and the bowl shape facilitating the capping to the surface of the virus particle [ 31 ]. …”

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“…Therefore, the straightforward strategy of mimicking receptor SA by carbohydrate-based analogs to block virus-receptor binding is difficult to achieve, since monovalent SA derivatives could hardly compete with native glycans [ 27 ]. As an alternative, great effort has been focused on designing 3D scaffolds carrying multivalent SA analogs to inhibit influenza virus infection [ 28 , 29 , 30 , 31 ].…”

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“…Incorporation of magnetic functionalities via encapsulation of superparamagnetic iron oxide nanoparticles in the PLGA cores allowed for virus isolation and enrichment, enabling enhanced pathogen detection via several different diagnostic assays. Towards enhancing red blood cell membrane-cloaked nanoparticles for influenza virus targeting, Nie et al demonstrated that particles with spikes between 5 and 10 nm could bind more effectively with influenza viruses as compared with particles with smooth surfaces upon cell membrane cloaking [129]. The enhanced binding is attributed to an interlocking mechanism between the spiky nanostructure and virus glycoproteins.…”