Antivirals are used to treat viral infections, and antibiotics are used to treat bacterial infections. However, the mechanisms of action and number of commercially available antivirals are very limited compared to those for antibiotics. Accordingly, our group is engaged in ongoing research to develop host-targeting antivirals for the virus infections. This work is primarily focused on the endoplasmic reticulum (ER) glucosidases involved in N-glycan synthesis as the host-dependent factors of viral infection. It is widely accepted that a key mechanism by which those inhibitors act as antivirals is their ability to disrupt virus glycoprotein folding via their inhibition of ER glucosidases. Importantly, very few virus strains are resistant to ER glucosidase inhibitors because ER glucosidase enzymes are not encoded on virus genomes. This avoids problems arising from resistance mutations occurring in the viral target. A number of ER glucosidase inhibitors with antiviral activity have been reported in the past, and several clinical trials of these have been performed. In this paper, we examine the factors preventing the development of these inhibitors as antivirals and our attempts to overcome them.
Abstract:In this study, all four stereoisomers of tryptoline or tetrahydro-β-carboline were synthesized in high yields by the catalyst-free amidation of methyl ester using methylamine under mild conditions. All isomers of the obtained amide and the precursor methyl ester were subjected to cell viability measurements on HeLa cells. The results indicated that the stereochemistry of the derivatives is clearly related to cell viability.
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