The SARS-CoV-2 spread quickly across the globe. The World Health Organization (WHO) on March 11 declared COVID-19 a pandemic. The mortality rate, hospital disorders and incalculable economic and social damages, besides the unproven efficacy of the treatments evaluated against COVID-19, raised the need for immediate control of this disease. Therefore, the current study employed in silico tools to rationally identify new possible SARS-CoV-2 main protease (Mpro) inhibitors. That is an enzyme conserved among the coronavirus species; hence, the identification of an Mpro inhibitor is to make it a broad-spectrum drug. Molecular docking studies described the binding sites and the interaction energies of 74 Mpro-ligand complexes deposited in the Protein Data Bank (PDB). A structural similarity screening was carried out in order to identify possible Mpro ligands that show additional pharmacological properties against COVID-19. We identified 59 hit compounds and among them, melatonin stood out due to its prominent immunomodulatory and anti-inflammatory activities; it can reduce oxidative stress, defence cell mobility and efficiently combat the cytokine storm and sepsis. In addition, melatonin is an inhibitor of calmodulin, an essential intracellular component to maintain angiotensin-converting enzyme 2 (ACE-2) on the cell surface. Interestingly, one of the most promising hits in our docking study was melatonin. It revealed better interaction energy with Mpro compared to ligands in complexes from PDB. Consequently, melatonin can have response potential in early stages for its possible effects on ACE-2 and Mpro, although it is also promising in more severe stages of the disease for its action against hyper-inflammation. These results definitely do not confirm antiviral activity, but can rather be used as a basis for further preclinical and clinical trials.

<p class="MsoNormal" style="text-align: justify; text-indent: 35.45pt;">Introdução: armazenar medicamentos nos domicílios é prática comum da população brasileira, podendo representar um potencial <span style="text-indent: 35.45pt;">risco para o surgimento de agravos à saúde. Além disso, esses medicamentos são armazenados, freqüentemente, em ambientes </span><span style="text-indent: 35.45pt;">inadequados, propiciando diversas possibilidades de consumo irracional. Objetivo: avaliar os medicamentos estocados nos domicílios </span><span style="text-indent: 35.45pt;">em uma cidade do Paraná. Metodologia: foram visitados 31 domicílios e aos seus responsáveis foi aplicado um questionário </span><span style="text-indent: 35.45pt;">padrão semiestruturado. Resultados: foram encontrados 159 medicamentos sendo destes, 33% de anti-inflamatórios, sendo a via </span><span style="text-indent: 35.45pt;">de administração mais citada a oral (74%). Os locais de armazenamento mais frequentemente encontrados foram cozinhas (48%) </span><span style="text-indent: 35.45pt;">seguido dos dormitórios (33%). É válido lembrar que 32,35% dos medicamentos estavam em locais expostos à umidade, 23,52% </span><span style="text-indent: 35.45pt;">acesso à crianças, 20,58% à luz e insetos, 14,70% ao calor e 8,82% à radiação. Conclusão: assim, foi possível observar que a farmácia </span><span style="text-indent: 35.45pt;">caseira está presente na maioria das residências visitadas. E, levando-se em consideração que o profissional do medicamento é o </span><span style="text-indent: 35.45pt;">farmacêutico, pode-se constatar a importância de uma maior atuação deste junto à população. Pois, como mostra claramente este </span><span style="text-indent: 35.45pt;">trabalho, a população estudada armazena e utiliza muitos medicamentos e, portanto necessita de orientações, sobre seus usos, </span><span style="text-indent: 35.45pt;">formas de armazenamento entre outras atribuições.</span></p>

Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wild-type mice were treated with prazosin 12 hours after CLP or NOS-2 inhibitor, 30 min before and 6 and 12 hours after CLP. In vivo experiments and biochemistry assays were performed 24 hours after CLP. Sepsis decreased the systemic mean arterial pressure and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decreased in GRK2 level associated to an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400W. Treatment of non-septic mice with a NO donor reduced GRK2 content in the kidney. Therefore, our results show that a NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density, probably. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.

We have shown that arteries present differential responses to α1 adrenergic receptors (α1ARs) agonists in sepsis (Bernardelli et al., Can J Physiol Pharmacol, 94, 1227–36, 2016). Indeed, in animals subjected to the cecal ligation and perforation (CLP) model of sepsis, activation of α1ARs by norepinephrine (NE) results in a small degree of hyporesponsiveness, compared with the responses generated by phenylephrine (PE). It is well known that increased amounts of nitric oxide (NO) are produced in sepsis. NO plays a crucial role in septic vasoplegia, so we hypothesized that α1ARs agonists could differentially modulate the activity of NO synthases (NOS). Here, endothelium‐intact aortic rings from male Wistar rats subjected to CLP were studied in organ baths at 6 h after the septic insult. Control experiments were conducted with arteries from naïve animals. The effects of increasing concentrations (1 nM–300 mM) of PE and NE were evaluated in preparations previously incubated with L‐NAME (a non‐selective inhibitor of NOS; 100 μM), 1400W (a selective inhibitor of the inducible isoform of NOS; 10 μM), or S‐Methyl‐L‐thiocitrulline (a selective inhibitor of the neuronal isoform of NOS; 10 μM). We also investigated the influence of sodium nitroprusside (SNP; 0.1 μM, during 30 min) in the responses of control arteries to PE and NE. Aortic sections were also evaluated in experiments using the fluorescent BODIPY® FL prazosin (QAPB) (250 nM) and DAF‐FM (10 μM). Incubation with L‐NAME increased the contractile effects of PE and NE in both the control and CLP group. On the other hand, both 1400W and S‐methyl‐L‐thiocitrulline had no influence in the effects of PE and NE in control preparations, and increased the responses to PE (but not to NE) from 1.31 ± 0.06 g in control to 2.24 ± 0.11 and 2.21 ± 0.14 g, respectively, in the CLP group (p < 0.05). The fluorescence of QAPB in aortic sections did not differ between the groups, regardless of the previous incubation with PE or NE, suggesting that there were no significant differences in the density of α1ARs between the groups. Besides, neither PE nor NE were able to increase NO production, as detected by the NO sensitive fluorescence probe DAF‐FM. Interestingly, incubation with SNP reduced the maximal contractile effect of NE and PE by 35 and 65%, respectively (p < 0.05). These results suggest that neither an impaired interaction of PE and NE with α1ARs nor a differential modulation of NO production account for the distinct degree of vascular hyporeactivity observed. Nevertheless, our findings reveal remarkable differences between the intracellular signaling activated by PE and NE, regarding their sensitivity to NO. The better comprehension of the behavior of α1ARs can allow the development of ligands with enhanced efficacy for the management of vasoplegia and hypotension in sepsis. Support or Funding Information Financial Support: CNPq (Brazil), with a Ph.D. fellowship to Bernardelli, A. K. This study was approved by the Animal Ethics Committee of UFSC (6327180718).

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