Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation.

Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.

MicroRNA-30 and 145 as Targets for the Treatment of Cardiovascular Diseases: Therapeutic Feasibility and Challenges.

Cardiovascular diseases (CVDs) are a group of non-communicable disorders of the heart and blood vessels. Although lifestyle changes as well as pharmacological treatments and surgical interventions are available in many countries, CVDs are still considered the number one cause of mortality worldwide. Hence, considering that most CVDs are caused by genetic and environmental imbalances, micro-RNAs (miRNAs or miRs) appear as a plausible therapeutic option for CVDs as they are able to regulate a wide number of genes due to multiple target sites in different genes. Since miRNA-30 and -145 have been shown to play critical roles in the cardiovascular system, acting as important regulators of many functions and biological processes, this review focuses on summarizing recent findings on their involvement in CVDs, mainly as targets for therapeutic intervention. Therefore, the biology, mechanisms of action and data on what has been discovered so far regarding miRNA-30 and 145 as therapeutic targets for CVDs are presented.

Predictive Value of Sirtuins in Acute Myocardial Infarction - Bridging the Bench to the Clinical Practice.

Acute myocardial infarction (AMI) is a non-transmissible condition with high prevalence, morbidity, and mortality. Different strategies for the management of AMI are employed worldwide, but its early diagnosis remains a major challenge. Many molecules have been proposed in recent years as predictive agents in the early detection of AMI, including troponin (C, T, and I), creatine kinase MB isoenzyme, myoglobin, heart-type fatty acid-binding protein, and a family of histone deacetylases with enzymatic activities named sirtuins. Sirtuins may be used as predictive or complementary treatment strategies and the results of recent preclinical studies are promising. However, human clinical trials and data are scarce, and many issues have been raised regarding the predictive values of sirtuins. The present review summarizes research on the predictive value of sirtuins in AMI. We also briefly summarize relevant clinical trials and discuss future perspectives and possible clinical applications.