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\begin{document}

\title{Circulating levels of ACE2 zinc-metalloprotease and zinc/albumin ratio
as potential biomarkers for a precision medicine approach to COVID-19}



\author[1]{Serena Benedetti}%
\author[1]{Davide Sisti}%
\author[2]{Daniela Vandini}%
\author[2]{Simone Barocci}%
\author[2]{Maurizio Sudano}%
\author[2]{Eugenio Carlotti}%
\author[1]{Loris Zamal}%
\affil[1]{University of Urbino Department of Biomolecular Sciences}%
\affil[2]{ASUR Marche Area Vasta 1}%


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  \date{May 21, 2024}


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\begin{abstract}
Background and Purpose: Highly mutable influenza is successfully
countered based on individual susceptibility and similar precision-like
medicine approach should be effective against SARS-COV-2. Among
predictive markers to bring precision medicine to COVID-19, circulating
ACE2 has potential features being upregulated in both severe COVID-19
and predisposing comorbidities. Spike SARS-CoVs were shown to induce
ADAM17-mediated shedding of enzymatic active ACE2, thus accounting for
its increased activity that has also been suggested to induce positive
feedback loops leading to COVID-19-like manifestations. For this reason,
pre-existing ACE2 activity and inhibition of ACE2/ADAM17
zinc-metalloproteases through zinc chelating agents have been proposed
to predict COVID-19 outcome before infection and to protect from
COVID-19, respectively. Since most diagnostic laboratories are not
equipped for enzymatic activity determination, other potential
predictive markers of disease progression exploitable by diagnostic
laboratories were explored. Experimental approach: Concentrations of
circulating ACE2 protein and activity, albumin and zinc were
investigated in healthy, diabetic (COVID-19-susceptible) and
SARS-CoV-2-negative COVID-19 individuals. Key Results: ACE2 both protein
levels and activity significantly increased in COVID-19 and diabetic
patients. Abnormal high levels of ACE2 characterised a subgroup
(16-19\%) of diabetics, while COVID-19 patients were characterised by
significantly higher zinc/albumin ratios, pointing to a relative
increase of albumin-unbound zinc species, such as ACE2-bound and free
zinc ones. Conclusions \& Implications: Data on circulating ACE2 levels
are in line with the hypothesis that they can drive susceptibility to
COVID-19 and elevated zinc/albumin ratios support the therapeutic use of
zinc chelating inhibitors of ACE2/ADAM17 zinc-metalloproteases in a
targeted therapy for COVID-19.%
\end{abstract}%



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