Studies on the QSAR of ACE Inhibitory Tripeptides with Proline as C-Terminal and Determination Inhibitory Activities

A database of 38 tripeptides with C-terminal proline was constructed to study QSAR of ACE inhibitory peptides. The model was established using PLS based on the three z-scores of 20 coded amino acids. The prediction ability of tripeptides model was improved with proline as terminal. The coefficient of determination(R2) and the cross validated coefficient(Q2LOO) of the model are 0.856 and 0.782 respectively. According to the model, two potential ACE inhibitory tripeptides IIP and IVP were synthesized. Their IC50(inhibitor concentration that reduced enzyme activity by 50%) were proved to be 1.58 and 1.39 μM respectively by direct spectrophotometric measurement, and they are very close to the predicted value by the model.

Evaluation of Peppermint Leaf Flavonoids as SARS-CoV-2 Spike Receptor-Binding Domain Attachment Inhibitors to the Human ACE2 Receptor: A Molecular Docking Study

Virtual screening is a computational technique widely used for identifying small molecules which are most likely to bind to a protein target. In the present work, a molecular docking study is carried out to propose potential candidates for preventing the RBD/ACE2 attachment. These candidates are sixteen different flavonoids present in the peppermint leaf. Results showed that Luteolin 7-O-neohesperidoside is the peppermint flavonoid with a higher binding affinity regarding the RBD/ACE2 complex (about -9.18 Kcal/mol). On the other hand, Sakuranetin presented the lowest affinity (about -6.38 Kcal/mol). Binding affinities of the other peppermint flavonoids ranged from -6.44 Kcal/mol up to -9.05 Kcal/mol. The binding site surface analysis showed pocket-like regions on the RBD/ACE2 complex that yield several interactions (mostly hydrogen bonds) between the flavonoid and the amino acid residues of the proteins. This study can open channels for the understanding of the roles of flavonoids against COVID-19 infection.

Remdesivir, dexamethasone and angiotensin-converting enzyme inhibitors use and mortality outcomes in COVID-19 patients with concomitant troponin elevation

BACKGROUND There are indications that viral myocarditis,demand ischemia,and renin-angio-tensin-aldosterone system pathway activation play essential roles in troponin elevation in coronavirus disease 2019(COVID-19)patients.Antiviral medications and steroids are used to treat viral myocarditis,but their effect in patients with elevated troponin,possibly from myocarditis,has not been studied.AIM To evaluate the effect of dexamethasone,remdesivir,and angiotensin-converting enzyme(ACE)inhibitors(ACEI)on mortality in COVID-19 patients with elevated troponin.METHODS Our retrospective observational study involved 1788 COVID-19 patients at seven hospitals in Southern California,United States.We did a backward selection Cox multivariate regression analysis to determine predictors of mortality in our study population.Additionally,we did a Kaplan Meier survival analysis in the subset of patients with elevated troponin,comparing survival in patients that received dexamethasone,remdesivir,and ACEI with those that did not.RESULTS The mean age was 66 years(range 20-110),troponin elevation was noted in 11.5%of the patients,and 29.9%expired.The patients'age[hazard ratio(HR)=1.02,P<0.001],intensive care unit admission(HR=5.07,P<0.001),and ventilator use(HR=0.68,P=0.02)were significantly associated with mortality.In the subset of patients with elevated troponin,there was no statistically significant difference in survival in those that received remdesivir(0.07),dexamethasone(P=0.63),or ACEI(P=0.8)and those that did not.CONCLUSION Although elevated troponin in COVID-19 patients has been associated with viral myocarditis and ACE II receptors,conventional viral myocarditis treatment,including antiviral and steroids,and ACEI did not show any effect on mortality in these patients.

Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19:A review

As of August 16,2021,there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease(COVID-19),and the pandemic remains a global challenge.To date,no effective and approved drugs are available for the treatment of COVID-19.Angiotensin-converting enzyme 2(ACE2)plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiological agent of COVID-19.Notably,ACE2 density is influenced by medical conditions,such as hypertension,or by drugs,including angiotensin-converting enzyme inhibitors(ACEIs)and angiotensin receptor blockers(ARBs),which can change the fate of SARS-CoV-2 infectivity.ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells.Different strategies aimed at blocking ACE2 with small molecules,peptides,and antibodies,or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2(hrsACE2)are currently under investigation.In this article,we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target.The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease.It has not yet been established whether hypertension and other comorbidities,independent of age,have a direct role in COVID-19.Therefore,the use of renin-angiotensin system inhibitors,ACEIs and ARBs,should not be discontinued during COVID-19 treatment.

Effects of Long-term Ramipril on Ventricular Remodeling,Cardiac Function and Survival in Rat Congestive Heart Failure after Myocardial Infarction

Objectives The purpose ofthis study was to investigate the effects of long-termramipril on ventricular remodeling, cardiac functionand survival in rat congestive heart failure after my-ocardial infarction. Methods Myocardial infarction(MI) was caused by ligation of the left anterior de-scending coronary artery in rats. 7 days after thesurgery, the surviving rats were randomly assigned tothe following treatment protocols: 1) MI ras with notherapy, 2) MI rats treated with ramipril 3 mg/kg perday, 3) Sham-operated control rats, and 4) Sham-op-erated rats treated with ramipril 3 mg/kg per day. At22 weeks, cardiac hemodynamic parameters such asMAP, LVSP, ±dP/dtmax and LVEDP were measured,and cardiac morphometric parameters such as HW,LVW and LVCA were measured, mRNA of cardiacmolecule genes, such as βMHC, BNP, collagen Ⅰ andⅢ, and TGF-β_1, were quantified, and survival rateswere calculated. Results Compared with sham-operated rats, MI rats without therapy showed significantincreases in cardiac morphological parameters as wellas in mRAN expressions of cardiac molecule genes(P<0.01); while their hemodynamic parameters weresignificantly impaired (P<0.01), and survival rateshortened (P<0.05). Compared with MI rats with notherapy, MI rats treated with ramipril showed signifi-cant attenuation of mRAN expressions of cardiacmolecule genes (P<0.01); while their hemodynamicparameters were significantly improved (P<0.05 or P<0.01), and survival rates prolonged (P<0.05). Con-clusions Treatment with long-term ramipril may im-prove LV remodeling, cardiac function and survival inrat congestive heart failure after MI.