RESUMO
Most viruses start their invasion by binding to glycoproteins' moieties on the cell surface (heparan sulfate proteoglycans [HSPG] or sialic acid [SA]). Antivirals mimicking these moieties multivalently are known as broad-spectrum multivalent entry inhibitors (MEI). Due to their reversible mechanism, efficacy is lost when concentrations fall below an inhibitory threshold. To overcome this limitation, we modify MEIs with hydrophobic arms rendering the inhibitory mechanism irreversible, i.e., preventing the efficacy loss upon dilution. However, all our HSPG-mimicking MEIs only showed reversible inhibition against HSPG-binding SARS-CoV-2. Here, we present a systematic investigation of a series of small molecules, all containing a core and multiple hydrophobic arms terminated with HSPG-mimicking moieties. We identify the ones that have irreversible inhibition against all viruses including SARS-CoV-2 and discuss their design principles. We show efficacy in vivo against SARS-CoV-2 in a Syrian hamster model through both intranasal instillation and aerosol inhalation in a therapeutic setting (12 h postinfection). We also show the utility of the presented design rules in producing SA-mimicking MEIs with irreversible inhibition against SA-binding influenza viruses.
RESUMO
We have demonstrated the design of a novel bifunctional catalyst that is based on an N-confused tetraphenylporphyrin (NCTPP) motif for the cycloaddition of an epoxide to carbon dioxide via cooperative activation of the epoxide through a Pd(ii) or Ni(ii) metal center and a peripheral benzoate moiety with percent conversions of up to 99% and TON = 7000.