biostudies-literatureNie CChina Scholarship CouncilFundamental Research Funds for the Central UniversitiesDeutsche ForschungsgemeinschaftAlexander von Humboldt-StiftungNational Key Research and Development Program of China Stem Cell and Translational ResearchState Key Laboratory of Polymer Materials EngineeringSichuan UniversityPetroChina Innovation Foundationeabd3803https://www.ebi.ac.uk/biostudies/studies/S-EPMC7775783biostudies-literatureUnknown7(1)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.Science advancesHeteromultivalent topology-matched nanostructures as potent and broad-spectrum influenza A virus inhibitors.PMC77757832019YFA0110601grant BL1514/12019YFA0110600sklpme2019-2-03BioSupraMolSFB 765Thousand Talents Recruitment ProgrammeCheng CHaag RNie CBlock SWolff TParshad BStadtmuller MKerkhoff YBhatia SAhmadi VWallert MfalseHeteromultivalent topology-matched nanostructures as potent and broad-spectrum influenza A virus inhibitors.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.2021-01-01T00:00:00Z2021 Jan2024-11-14T13:38:13.857Z2021-02-21T05:28:52ZS-EPMC77757833352384610.1126/sciadv.abd3803