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Znaczenie aktywności proteazy kapsydowej CP w rozwoju infekcji alfawirusowych

Torzyk Karolina, Skoreński Marcin, Sieńczyk Marcin

Wiadomości Chemiczne

2022

[Z] 76, 5-6

309--321

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.