Strategies for Targeting SARS CoV-2: Small Molecule Inhibitors-The Current Status.

Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. The clinical manifestations of this disease are pneumonia, lung injury, inflammation, and severe acute respiratory syndrome (SARS). Currently, there is no vaccine or effective pharmacological agents available for the prevention/treatment of SARS-CoV2 infections. Moreover, development of a suitable vaccine is a challenging task due to antibody-dependent enhancement (ADE) and Th-2 immunopathology, which aggravates infection with SARS-CoV-2. Furthermore, the emerging SARS-CoV-2 strain exhibits several distinct genomic and structural patterns compared to other coronavirus strains, making the development of a suitable vaccine even more difficult. Therefore, the identification of novel small molecule inhibitors (NSMIs) that can interfere with viral entry or viral propagation is of special interest and is vital in managing already infected cases. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, the development of novel inhibitors of ACE2/TMPRSS2 is likely to be beneficial in combating SARS-CoV-2 infections. However, the usage of ACE-2 inhibitors to block the SARS-CoV-2 viral entry requires additional studies as there are conflicting findings and severe health complications reported for these inhibitors in patients. Hence, the current interest is shifted toward the development of NSMIs, which includes natural antiviral phytochemicals and Nrf-2 activators to manage a SARS-CoV-2 infection. It is imperative to investigate the efficacy of existing antiviral phytochemicals and Nrf-2 activators to mitigate the SARS-CoV-2-mediated oxidative stress. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs.

Cardioprotective activity of silymarin in ischemia-reperfusion-induced myocardial infarction in albino rats.

BACKGROUND: There is comprehensive experimental and clinical evidence that either exogenous supplementation of natural antioxidants or augmentation of endogenous antioxidants attenuates myocardial infarction. OBJECTIVES: To investigate the effects of chronic administration of silymarin against ischemia-reperfusion-induced myocardial infarction in rats. METHODS: Silymarin was administered orally to Wistar albino rats (200 g to 250 g) in three different doses (100 mg/kg, 250 mg/kg and 500 mg/kg), by gastric gavage for one week. At the end of this period, control (ischemia-reperfusion) groups and silymarin-treated groups were subjected to 30 min occlusion of the left anterior descending coronary artery and thereafter reperfused for 4 h. RESULTS: Ischemia-reperfusion resulted in significant cardiac necrosis, indicated by elevated levels of serum marker enzymes such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, lactate dehydrogenase, creatine kinase-isoenzyme and creatine kinase. A significant rise in the end products of myocardial lipid peroxides (malondialdehydes [MDAs]), loss of antioxidative enzymes (superoxide dismutase, catalase, glutathione S-transferase and reduced glutathione) and increased levels of myeloperoxidase in heart tissue were observed in the animals subjected to in vivo myocardial ischemia-reperfusion injury. Infarct size was measured by using the staining agent 2,3,5-triphenyltetrazolium chloride. A lead II electrocardiogram was monitored at various intervals throughout the experiment. DISCUSSION: The present study showed that silymarin protected the endogenous antioxidant enzymes, suppressed the neutrophil infiltration during ischemia-reperfusion and limited the infarct size, with concomitant reduction in serum MDA, tissue MDA and serum marker enzymes in rats subjected to 30 min coronary artery occlusion followed by 4 h of reperfusion. Pretreatment with silymarin also protected rat hearts from a further drop in mean arterial blood pressure during reperfusion, and restored heart rate at the end of the reperfusion period. CONCLUSIONS: The present study suggests that the phytochemical silymarin has cardioprotective activity against ischemia-reperfusion-induced myocardial infarction in rats.

Cardioprotective activity of alcoholic extract of Tinospora cordifolia in ischemia-reperfusion induced myocardial infarction in rats.

It has been suggested that the beneficial effects of reperfusing the myocardium might be in part reversed by the occurrence of reperfusion injury. Oxidative stress was suggested to be implicating in the pathogenesis of ischemia-reperfusion (I/R) injury. Many antioxidative plants were shown to be cardioprotective in experimental models of myocardial ischemia-reperfusion (I/R) injury. The present study was designed to investigate the effects of pretreatment with alcoholic extract of Tinospora cordifolia in an in vivo rat model. The model adopted was that of surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was measured by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically by the methods developed by Yagi and Ohkawa et al. respectively. A lead II electrocardiogram was monitored at various intervals throughout the experiment. A dose dependent reduction in infarct size and in lipid peroxide levels of serum and heart tissue were observed with the prior treatment of T. cordifolia with various doses for 7 d compared to control animals. Hence, the present study suggests the cardioprotective activity of T. cordifolia in limiting ischemia-reperfusion induced myocardial infarction.

Anti-inflammatory activity of a new sphingosine derivative and cembrenoid diterpene (lobohedleolide) isolated from marine soft corals of Sinularia crassa TIXIER-DURIVAULT and Lobophytum species of the Andaman and Nicobar Islands.

The aim of this study is to determine the anti-inflammatory activity of a new sphingosine derivative (1) and cembrenoid diterpene (lobohedleolide) (2) isolated from the soft corals of Sinularia crassa and Lobophytum species respectively, collected on the coasts of Andaman and Nicobar Islands. The anti-inflammatory activity was evaluated using carrageenin-induced rat hind paw edema model for acute inflammation and cotton pellet granuloma model for chronic inflammation. Indomethacin was used as a standard drug in this study. Both the sphingosine derivative (1) and the cembrenoid diterpene (2) produced the maximum effect at a dose of 10 mg/kg and this is comparable to that of indomethacin (2 mg/kg, p<0.001). The observed anti-inflammatory activity is almost identical in both the types of experimental inflammation.