Peptidomimetic inhibitors OF SARS-CoV-2 3CLpro, protease responsible for replication and coronavirus infection

Peptidomimetici su molekule koje svojom 3D-strukturom oponašaju bioaktivnu konformaciju prirodnih peptida, a odlikuju se povećanom proteolitičkom stabilnošću i selektivnošću prema receptorima te većom bioraspoloživošću u odnosu na prirodne peptide. Nakon ulaska SARS-CoV-2 u stanicu, virusna RNA translatira se na ribosomima, a virusna proteaza SARS-CoV-2 3CLpro sudjeluje u hidrolizi nastalih poliproteina nakon čega slijedi tvorba novih viriona. Stoga se inhibicijom virusne proteaze onemogućava njegova replikacija. Opisani su peptidomimetički inhibitori virusne proteaze u kojima je aminokiselinska sekvencija iz prirodnog supstrata modificirana funkcijskom skupinom (aldehid, α-ketoamid ili Michaelov akceptor) pomoću koje s aktivnim mjestom enzima uspostavlja kovalentnu vezu. Time se kompleks inhibitora i proteaze dodatno stabilizira što dovodi do inhibicije enzima odnosno replikacije virusa. Usporedbom kristalnih struktura kompleksâ peptidomimetičkih inhibitora i SARS-CoV-2 3CLpro te evaluacijom njihovog inhibitornog djelovanja, najučinkovitijim inhibitorima pokazali su se peptidomimetici s umetnutom α-ketoamidnom skupinom.Peptidomimetics are molecules whose 3D structure mimics the bioactive conformation of natural peptides. They are characterized by higher proteolytic stability, selectivity for receptors and higher bioavailability compared to natural peptides. After SARS- CoV-2 enters the cell, viral RNA is translated on the ribosomes, and the viral protease SARS- CoV-2 3CLpro is involved in the hydrolysis of the resulting polyproteins followed by the formation of new virions. Therefore, inhibition of the viral protease prevents viral replication. Peptidomimetic inhibitors of viral protease are described in which the amino acid sequence of a natural substrate is modified by a functional group (aldehyde, α-ketoamide or Michael acceptors) to allow covalent binding with the enzyme active site. This further stabilizes the complex of inhibitor and protease, resulting in inhibition of the enzyme or replication of the virus. Comparison of the crystal structures of the complex of peptidomimetic inhibitors and SARS-CoV-2 3CLpro and evaluation of their inhibitory activity revealed that peptidomimetics with inserted α-ketoamide group are the most efficient