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Background: Many stresses trigger cellular senescence, including telomere shortening, oncogene activation, DNA-replication stress, oxidative stress, and resistance to apoptosis. Forkhead box protein O4 (FOXO4) plays a pivotal role in cellular senescence, by binding to and inactivating p53, thereby leading to cellular senescence and inhibiting p53 mediated apoptosis. As a result, misregulation of FOXO4-p53 is linked to numerous diseases including cancers and aging-related diseases, pulmonary fibrosis and neurodegenerative diseases. Targeting of the FOXO4-p53 interface has been accomplished using a synthetic D retro inverse peptide (DRI), however recognition of the key molecular drivers of the interactions remains unknown. Understanding these interactions on a molecular level could lead to the development of small compounds, with enhanced pharmacological qualities, such as high stability, membrane permeability, and oral bioavailability, that mimics the activity of the DRI peptide. Methods and Results: Using an in silico model of the FOXO4-p53 interaction, we designed shorter peptides within the DRI to identify the key interactions. A biophysical assay demonstrates these shorter peptides retain strong binding affinity to p53, suggesting that the DRI's hot spot is located within these peptides. Conclusions: Taken together, this data provides information at the molecular level that is key to understanding the interplay of two proteins responsible for cellular senescence and provides the basis for the design of small molecules to inhibit this interaction.

At the end of 2019, Sars-CoV-2 was identified and has since spread in the world. Coronavirus is commonly caused by the upper respiratory tract and severe acute respiratory syndrome in humans. Due to the novel nature of the virus and high mortality among high-risk people, today health care providers used several medications with different mechanisms to overcome this virus. The course of COVID-19 represents three stages that have different symptoms and used different drugs depends on each stage. Ultimately the minority of patients progress to stage III with high mortality. The aim of this study is a comprehensive review of COVID-19 adjuvant therapies. We explained the current study on the use of Glucocorticoids, Interferon, Vitamin C, Tocilizumab, Anakinra, Pentoxifylline, IVIG, Allopurinol, Ivermectin, and Selenium in sepsis, pneumonia, and ARDS and we suggested a new protocol for prescribing each medication currently used in COVID-19 Outbreak. At the end of 2019, Sars-CoV-2 was identified and has since spread in the world. Coronavirus is commonly caused by the upper respiratory tract and severe acute respiratory syndrome in humans. Due to the novel nature of the virus and high mortality among high-risk people, today health care providers used several medications with different mechanisms to overcome this virus. The course of COVID-19 represents three stages that have different symptoms and used different drugs depends on each stage. Ultimately the minority of patients progress to stage III with high mortality. The aim of this study is a comprehensive review of COVID-19 adjuvant therapies. We explained the current study on the use of Glucocorticoids, Interferon, Vitamin C, Tocilizumab, Anakinra, Pentoxifylline, IVIG, Allopurinol, Ivermectin, and Selenium in sepsis, pneumonia, and ARDS and we suggested a new protocol for prescribing each medication currently used in COVID-19 Outbreak.

The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein-protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.

Arginine metabolism mediated by arginases plays a critical role in cell and tissue function. The arginine hydrolysis is deeply involved in the urea cycle, which helps the kidney excrete ammonia from blood. Upregulation of arginases affects microenvironment stability due to the presence of excess urea in blood. To regulate the arginase activities properly, a synthetic peptide based on the structure of human arginase I was designed and assessed. Preliminary data shows it inhibits human arginase I and II with an IC50 of 2.4 ± 0.3 and 1.8 ± 0.1 mmol, respectively. Our kinetic analysis indicates the inhibition is not competitive with substrate – suggesting an allosteric mechanism. This result provides a step towards specific inhibitors design. Supplementary Information The online version contains supplementary material available at 10.1007/s11033-021-06176-5.

Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), also known as Rhodanese, is a mitochondrial enzyme which catalyzes the transfer of sulfur in several molecular pathways. After its initial identification as a cyanide detoxification enzyme, it was found that its functions also include sulfur metabolism, modification of iron-sulfur clusters and the reduction of antioxidants glutathione and thioredoxin. TST deficiency was shown to be strongly related to the pathophysiology of metabolic diseases including diabetes and obesity. This review summarizes research related to the enzymatic properties and functions of TST, to then explore the association between the effects of TST on mitochondria and development of diseases such as diabetes and obesity.