SARS-CoV-2 proteins bind heme and hemoglobin

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), has led to a global crisis that included collapsing healthcare systems and shut-down communities, producing considerable economic burden. Despite the number of effective vaccines quickly implemented, the emergence of new variants is a primary concern. The scientific community undertook a rapid response to better study this new virus. However, critical questions about viral protein-protein interactions and mechanisms of its physiopathology are still unclear. Although severe COVID-19 was associated with hematological dysfunctions, scarce experimental data were produced about iron dysmetabolism and the viral proteins possible interaction with hemoglobin (Hb) chains. This work demonstrates the binding of SARS-CoV-2 proteins to hemin and Hb using a multimethodological approach. In silico analysis indicated binding motifs between a cavity in the viral nucleoprotein and hemoglobins porphyrin coordination region. Different hemin binding capacities of mock and SARS-CoV-2-infected culture extracts were noticed using gel electrophoresis and TMB staining. Hemin-binding proteins were isolated from SARS-CoV-2-infected cells by affinity chromatography and identified by shotgun proteomics, indicating that structural (nucleoprotein, spike, and membrane protein) and non-structural (Nsp3 and Nsp7) viral proteins interact with hemin. In vitro analyses of virus adsorption to host cells and viral replication studies in Vero cells demonstrated inhibitory activities - at different levels - by hemin, protoporphyrin IX (PpIX) Hb. Strikingly, free Hb at 1M suppressed viral replication (99 %), and its interaction with SARS-CoV-2 was localized to the RBD region of the Spike protein. The findings showed clear evidence of new avenues to disrupt viral replication and understand virus physiopathology that warrants further investigation.

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors, such as atazanavir (ATV). ATV is of high interest because of its bioavailability within the respiratory tract. Our results show that ATV could dock in the active site of SARS-CoV-2 Mpro, with greater strength than LPV. ATV blocked Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells, human pulmonary epithelial cell line and primary monocytes, impairing virus-induced enhancement of IL-6 and TNF- levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.

Weathering processes and dating of soil profiles from São Paulo State, Brazil, by U-isotopes disequilibria.

This study reports the use of the U-series radionuclides 238U and 234U for dating two soil profiles. The soil horizons developed over sandstones from Tatuí and Pirambóia formations at the Paraná sedimentary basin, São Paulo State, Brazil. Chemical data in conjunction with the 234U/238U activity ratios (AR's) of the soil horizons allowed investigating the U-isotopes mobility in the shallow oxidizing environment. Kaolinization and laterization processes are taking place in the profiles sampled, as they are especially common in regions characterized by a wet and dry tropical climate and a water table that is close to the surface. These processes are implied by inverse significant correlations between silica and iron in both soil profiles. Iron oxides were also very important to retain uranium in the two sites investigated, helping on the understanding of the weathering processes acting there. 238U and its progeny 234U permitted evaluating the processes of physical and chemical alteration, allowing the suggestion of a possible timescale corresponding to the Middle Pleistocene for the development of the more superficial soil horizons.

Reverse T3 as a parameter of myocardial function impairment in heart failure.

Sick Euthyroid Syndrome (SES) has been defined as low T(3) levels in the presence of normal TSH concentrations. The purpose of this study was to assess the relationship between heart failure functional classes (NYHA) and the presence of SES, as well as to estimate an index of myocardial function impairment (MFI). Forty-six patients were evaluated and 66 clinical laboratory assessments were performed. Clinical laboratory assessment reports (CLAR) were categorized according to heart failure functional class. The levels of rT(3) and fT(3)/rT(3) ratios were significantly higher and lower in class IV, respectively. In all CLAR reviewed, rT(3) positively correlated with functional classes II, III and IV. By adding the mean of the rT3 values found in Group I to one SD, MFI was estimated as 0.47 µg/mL. In 24 of the 66 CLAR reviewed MFI>0.47 µg/mL. Of these 24 CLAR, 92% were in Group II, and 8% were in Group I. MFI was low in 42 CLAR; 74% in Group II and 26% in Group I. MFI and rT(3) levels could be used for the evaluation of the prognosis of patients with heart failure in addition to (or even replacing) NYHA functional classification given that rT(3)>MFI suggests that the patient has a 92% possibility to be in NYHA functional class III or IV.