Biology subjects

Perea, D.

Publications and source records attributed to Perea, D..

3 recordsLinked to original sources

bioRxiv2022

Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication

As SARS-CoV-2 triggered a global health crisis, there is an urgent need to provide patients with safe, effective, accessible, and preferably oral therapeutics for COVID-19 that complement mRNA vaccines. Zinc compounds are widely known for their antiviral properties. Therefore, we have prepared a library of zinc complexes with pyrithione (1-hydroxy-2(1H)-pyridinethione) and its analogues, all of which showed promising in vitro inhibition of cathepsin L, an enzyme involved in SARS-CoV-2 entry, and PLPro, an enzyme involved in SARS-CoV-2 replication both in (sub)micromolar range. Zinc pyrithione 1a is a well-established, commercially available antimicrobial agent and was therefore selected for further evaluation of its SARS-CoV-2 entry and replication inhibition in an ex vivo system derived from primary human lung tissue. Our results suggest that zinc pyrithione complex 1a provides a multitarget approach to combat SARS-CoV-2 and should be considered for repurposing as a potential therapeutic against the insidious COVID-19 disease. Featured imageIn our study, we show that zinc pyrithione holds immense potential for the development of a possible out-patient treatment for SARS-CoV-2 due to its inhibition of viral entry and replication. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/482819v1_ufig1.gif" ALT="Figure 1"> View larger version (111K): org.highwire.dtl.DTLVardef@2da94corg.highwire.dtl.DTLVardef@1c5da6borg.highwire.dtl.DTLVardef@86acd6org.highwire.dtl.DTLVardef@1bd4c3d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2021

Entrectinib - a SARS-CoV-2 inhibitor in Human Lung Tissue (HLT) cells

Since the start of the COVID-19 outbreak, pharmaceutical companies and research groups have focused on the development of vaccines and antiviral drugs against SARS-CoV-2. Here, we apply a drug repurposing strategy to identify potential drug candidates that are able to block the entrance of the virus into human cells. By combining virtual screening with in vitro pseudovirus assays and antiviral assays in Human Lung Tissue (HLT) cells, we identify entrectinib as a promising antiviral drug. We found that part of the antiviral action of entrectinib is mediated by a non-specific mechanism, likely occurring at the viral membrane level. Such a profile could provide entrectinib with protection against the development of drug resistance by emerging SARS-CoV-2 variants.

cell biology↗

bioRxiv2021

Novel Human Lung Tissue Model for the Study of SARS-CoV-2 Entry, Inflammation and New Therapeutics

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/440731v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@96abf6org.highwire.dtl.DTLVardef@1f3cfe3org.highwire.dtl.DTLVardef@1d55fdborg.highwire.dtl.DTLVardef@1884cd6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsEx vivo physiological systems for the study of SARS-CoV-2-host interactions are scarce. Here, we establish a method using primary human lung tissue (HLT) cells for the rapid analysis of cell tropism and identification of therapeutics. O_LIHLT cells preserve main cell subpopulations, including alveolar type-2 cells, and expression of SARS-CoV-2 entry factors ACE2, CD147, TMPRSS2 and AXL. C_LIO_LIHLT cells are readily susceptible to SARS-CoV-2 infection without the need of cell isolation or further cell differentiation. C_LIO_LIAntiviral testing in HLT cells allows the rapid identification of new drug candidates against SARS-CoV-2 variants, missed by conventional systems. C_LIO_LILocal inflammation is supported in HLT cells and offers the identification of relevant anti-inflammatory compounds for SARS-CoV-2 infection. C_LI

microbiology↗