Anti‐Coronaviral Nanocluster Restrain Infections of SARS‐CoV‐2 and Associated Mutants through Virucidal Inhibition and 3CL Protease Inactivation

Abstract

Antivirals that can combat coronaviruses, including SARS‐CoV‐2 and associated mutants, are urgently needed but lacking. Simultaneously targeting the viral physical structure and replication cycle can endow antivirals with sustainable and broad‐spectrum anti‐coronavirus efficacy, which is difficult to achieve using a single small‐molecule antiviral. Thus, a library of nanomaterials on GX_P2V, a SARS‐CoV‐2‐like coronavirus of pangolin origin, is screened and a surface‐functionalized gold nanocluster (TMA‐GNC) is identified as the top hit. TMA‐GNC inhibits transcription‐ and replication‐competent SARS‐CoV‐2 virus‐like particles and all tested pseudoviruses of SARS‐CoV‐2 variants. TMA‐GNC prevents viral dissemination through destroying membrane integrity physically to enable a virucidal effect, interfering with viral replication by inactivating 3CL protease and priming the innate immune system against coronavirus infection. TMA‐GNC exhibits biocompatibility and significantly reduces viral titers, inflammation, and pathological injury in lungs and tracheas of GX_P2V‐infected hamsters. TMA‐GNC may have a role in controlling the COVID‐19 pandemic and inhibiting future emerging coronaviruses or variants.

Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery

“…SARS-CoV-2 trVLP was not a pseudovirus but a live virus model that was used to test the anti-SARS-CoV-2 abilities of drugs 30 . This model has been widely used in published studies 20 , 66 – 69 . SARS-CoV-2 trVLP is scientifically reliable model to evaluate the activity of drugs against SARS-CoV-2.…”

“…Downstream biosynthetic pathways of BIA dimers including cepharanthine ( 1 ), tetrandrine ( 3 ), and berbamine ( 10 ) remain largely unexplored. Given the potent anti-SARS-CoV-2 property of cepharanthine ( 1 ), investigating whether its analogs have antiviral activity would be helpful for new broad-spectrum antiviral drug development 20 .…”

Pathogen‐binding nanoparticles to inhibit host cell infection by heparan sulfate and sialic acid dependent viruses and protozoan parasites

“…A recent study that highlights the issue of interconnected multifunctionality used Au nanoclusters with terminal ammonium groups (TMA-GNCs). 73 The inhibition mechanism was found to be virucidal but functioning through multi-fold mechanisms by concurrently attacking and destroying the virus itself, reducing coronavirus protease 3CL pro activity, and activating antiviral immune responses. Similarly, other metal-based NP types can have some effect on viral attachment/entry, but it is often combined with other effects on host cells.…”

“…These virucidal NPs not only bind to viruses but also inactivate them by disrupting the viral structure. 25,43,49,54,57,73 Compared to viruses, protozoan parasites are much more complex unicellular eukaryotic pathogens with thousands of proteins involved in their life cycles. However, the involvement of the same HS/SA attachment receptors in host cell invasion of various obligate intracellular protozoan parasites was confirmed as summarized herein.…”