The Role of TMPRSS2 and TMPRSS2- Inhibitors in Cell Entry Mechanism of COVID-19

The enzymes trypsin, furine and other proprotein convertases, cathepsin, transmembrane proteases (TMPRSS) and elastases play a role in the cell entry of coronaviruses (Coronaviridae). The proteases TMPRSS2 and TMPRSS11a, which are abundant in the respiratory tract and expressed on cell surfaces, promote the entry of SARS-CoV-1 viruses. For the TMPRSS protease TMPRSS11d - also known as human airway trypsin-like protease (HAT) - a proteolytic activation of the S- protein of SARS-CoV-1 was demonstrated. TMPRSS2, in turn, complexes with the ACE2 receptor, which allows efficient penetration of the virus directly at the cell surface. TMPRSS2 and TMPRSS11D activate the S protein by cleaving it into the S1 and S2 subunits, thus allowing endosome-independent cell entry at the cell membrane. Virus-based therapies include monoclonal antibodies, antiviral peptides that dock to the S protein of viruses, viral nucleic acid synthesis inhibitors and inhibitors for docking to other viral structures and accessory proteins.

Antimicrobial Drug Interactions: Systematic Evaluation of Protein and Nucleic Acid Synthesis Inhibitors

Antimicrobial multidrug resistance and its transmission among strains are serious problems. Success rate is decreased and treatment options are narrowed due to increasing bacterial multidrug resistance. On the other hand, the need for long-term efforts to discover new antibiotics and difficulties finding new treatment protocols make this problem more complex. Combination therapy, especially with synergistic use of antimicrobials is a rational treatment option with huge benefits. Thus, screening antibiotic interactions is crucial for finding better treatment options. Clinicians currently use combinatorial antibiotic treatment as an effective treatment option. However, antibiotics can show synergistic or antagonistic interactions when used together. In our study, we aimed to investigate interactions of antibiotics with different mechanisms of action. Antibiotics, which act as protein synthesis inhibitors (P) and nucleic acid synthesis inhibitors (N) were used in our study. We tested 66 (PN), 15 (NN), and 55 (PP) drug pairs on the Escherichia coli strain. The Loewe additivity model was used and alpha scores were calculated for analysis of interactions of drug combinations. Drug interactions were categorized as synergistic or antagonistic. Accordingly, pairwise combinations of protein synthesis inhibitors (PP) showed stronger synergistic interactions than those of nucleic acid synthesis inhibitors (NN) and nucleic acid synthesis–protein synthesis inhibitors (PN). As a result, the importance of mechanisms of action of drugs is emphasized in the selection of synergistic drug combinations.

Effect of Alachlor, Propachlor, and Prynachlor on GA3-induced Production of Protease and α-Amylase

Alachlor [2-chloro-2′,6′-diethyl-N(methoxymethyl)-acetanilide], propachlor (2-chloro-N-isopropylacetanilide) and prynachlor [2-chloro-N-(1-methyl-2-propynyl)acetanilide], inhibited gibberellic acid (GA3),-induced production of protease and α-amylase in deembryonated barley (Hordeum vulgareL, ‘Schuyler’) seed. Production of protease was more sensitive to these herbicides than α-amylase. The degree of inhibition of protease and α-amylase production caused by alachlor was equivalent to that caused by cycloheximide, puromycin and actinomycin-D, known protein and nucleic acid synthesis inhibitors. Higher GA3concentrations reversed the inhibition of protease and α-amylase synthesis caused by alachlor but did not reduce the effect of alachlor on barley seed germination and growth. It is concluded that the inhibition of protease and α-amylase production by alachlor is perhaps only one of several effects on early seed germination and seedling development.

Studies on conidial germination and appressorium formation by Colletotrichum trifolii Bain & Essary

Conidial germination of Colletotrichum trifolii was affected by concentrations of Tween 20 (polyoxyethylene sorbitan monolaurate). The highest rate of germination and appressorium formation was obtained in 0.083% Tween 20.Appressorium formation was more sensitive to temperature than was germination. The percentage of germinated spores which formed an appressorium was reduced when the spore suspensions were incubated for 24 h at incubation temperatures above 27 °C. Appressorium formation also was reduced when conidia were exposed, in culture or in suspension, to 35 °C for short periods. Similarly, germination was reduced with heat exposure, but at longer exposures than those necessary to reduce appressorium formation. Spores in suspension responded to a shorter heat exposure (4 h) than spores in culture.The reduced atmospheric CO2 level did not affect the amount of germination or appressorium formation. However, cell walls of appressoria produced in an atmosphere low in CO2 were thin-walled and without the brown pigment characteristic of normal appressoria.Protein synthesis inhibitors (cycloheximide and p-fluorophenylalanine) blocked both germination and appressorium formation. Nucleic acid synthesis inhibitors were either partially effective or ineffective and their mode of action in C. trifolii is unknown.