Phosphonate inhibitors of West Nile virus NS2B/NS3 protease

West Nile virus (WNV) is a member of the flavivirus genus belonging to the Flaviviridae family. The viral serine protease NS2B/NS3 has been considered an attractive target for the development of anti-WNV agents. Although several NS2B/NS3 protease inhibitors have been described so far, most of them are reversible inhibitors. Herein, we present a series of α-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. The most potent inhibitor identified was Cbz-Lys-Arg-(4-GuPhe)P(OPh)2 displaying Ki and k2/Ki values of 0.4 µM and 28 265 M−1s−1, respectively, with no significant inhibition of trypsin, cathepsin G, and HAT protease

Development of an SPR imaging biosensor for determination of cathepsin G in saliva and white blood cells

Cathepsin G (CatG) is an endopeptidase that is associated with the early immune response. The synthetic compound cathepsin G inhibitor I (CGI-I) was tested for its ability to inhibit the activity of CatG via a new surface plasmon resonance imaging assay. CGI-I was immobilized on the gold surface of an SPR sensor that was first modified with 1-octadecanethiol. A concentration of CGI-I equal to 4.0 μg·mL-1 and a pH of 8.0 were found to give the best results. The dynamic response of the sensor ranges from 0.25 to 1.5 ng·mL-1, and the detection limit is 0.12 ng·mL-1. The sensor was applied to detect CatG in human saliva and white blood cells

The Fellowship of Privileged Scaffolds—One Structure to Inhibit Them All

Over the past few years, the application of privileged structure has emerged as a powerful approach to the discovery of new biologically active molecules. Privileged structures are molecular scaffolds with binding properties to the range of different biological targets. Moreover, privileged structures typically exhibit good drug-like properties, thus assuring more drug-like properties of modified compound. Our main objective is to discuss the privileged structures used for the development of antiviral agents

The role of capsid protease CP activity in the development of alphaviral infections

Alphaviruses belong to the worldwide distributed Togaviridae family and Alphavirus genus. They are spherical, enveloped, single-stranded RNA arthropodborne viruses. Alphaviruses are mostly transmitted by mosquitoes (Aedes spp. and Anopheles spp.) and are geographically distributed in restricted areas where appropriate vectors are present (Fig.1.). The most recognized members of this genus are Sindbis (SINV), Semliki Forest (SFV), Venezuelan equine encephalitis (VEEV), Ross River (RRV), and Chikungunya (CHIKV) viruses. Alphaviruses are infection agents for humans and many animals. Clinically, most human infections with arthritogenic alphaviruses are associated with symptoms such as fever, headache, joint pain, rash, chronic arthritis, and encephalitis. Major events during the alphaviral infection are virus entry, replication, assembly, and budding of new virions. Alphaviral RNA encodes four nonstructural and five structural proteins. Nonstructural proteins are mainly involved in the replication process and virus pathogenesis, while structural proteins form new virions. Both groups of viral proteins are produced as single polyproteins which undergo autoproteolytic maturation. This process is carried out by the two viral proteases, cysteine protease nsP4 and C protein serine protease (CP), and is considered to be critical for virus replication. The capsid protease CP is a chymotrypsin-like serine protease with the catalytic triad including His145, Asp167, and Ser219. What is important, after a suicidal autoproteolytic event the side chain of Trp267 remains bound in a hydrophobic S1 pocket thus inhibiting further trans-proteolytic activity. Alphaviral capsid protein undergoes a single proteolytic reaction before maturation and then, after selfinactivation, it assembles to form a viral capsid shell. Inhibitors of the capsid protease have significant antiviral activity. Compounds belonging to this group can be good candidates for new antiviral drugs