Characterization of the Modulatory Effect of Hydroxychloroquine on ACE2 Activity: New Insights in relation to COVID-19

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dc.contributor.authorTichauer, Juan E.
dc.contributor.authorSoto, Dagoberto
dc.contributor.authorAndresen, Max
dc.date.accessioned2025-01-20T22:11:16Z
dc.date.available2025-01-20T22:11:16Z
dc.date.issued2021
dc.description.abstractChloroquine (CQ) and hydroxychloroquine (HCQ) have shown the ability to inhibit in vitro viral replications of coronaviridae viruses such as SARS-CoV and SARS-CoV-2. However, clinical trial outcomes have been disparate, suggesting that CQ and HCQ antiviral mechanisms are not fully understood. Based on three-dimensional structural similarities between HCQ and the known ACE2 specific inhibitor MLN-4760, we compared their modulation on ACE2 activity. Here we describe, for the first time, in a cell-free in vitro system that HCQ directly and dose-dependently inhibits the activity of recombinant human ACE2, with a potency similar to the MLN-4760. Further analysis suggests that HCQ binds to a noncompetitive site other than the one occupied by MLN-4760. We also determined that the viral spike glycoprotein segment that comprises the RBD segment has no effect on ACE2 activity but unexpectedly was able to partially reverse the inhibition induced by HCQ but not that by MLN-4760. In summary, here we demonstrate the direct inhibitory action of HCQ over the activity of the enzyme ACE2. Then, by determining the activity of ACE2, we reveal that the interaction with the spike protein of SARS-CoV-2 leads to structural changes that at least partially displace the interaction of the said enzyme with HCQ. These results may help to explain why the effectiveness of HCQ in clinical trials has been so variable. Additionally, this knowledge could be used for to develop techniques for the detection of SARS-CoV-2.
dc.description.funderIntensive Care Department, Facultad de Medicina, Pontificia Universidad Catolica de Chile
dc.fuente.origenWOS
dc.identifier.doi10.1155/2021/6614000
dc.identifier.eissn2314-6141
dc.identifier.issn2314-6133
dc.identifier.urihttps://doi.org/10.1155/2021/6614000
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94401
dc.identifier.wosidWOS:000683451300001
dc.language.isoen
dc.revistaBiomed research international
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleCharacterization of the Modulatory Effect of Hydroxychloroquine on ACE2 Activity: New Insights in relation to COVID-19
dc.typeartículo
dc.volumen2021
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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