Gs-441524 is a small molecule, known as a nucleoside triphosphate competitive inhibitor, which shows strong antiviral activity against many RNA viruses. It can inhibit the replication of several different types of RNA viruses, such as severe acute respiratory syndrome (SARS) coronavirus, Middle East respiratory syndrome virus, Ebola virus, Lassa fever virus, Junin virus, and respiratory syncytial virus, and has low cytotoxicity in a wide range of cell lines.
Action mechanism of gs-441524
Gs-441524 is phosphorylated into nucleoside monophosphate (NMP) by cell kinase in cells and then transformed into an active triphosphate metabolite (NTP structural analog). In viral RNA synthesis, active NTP structural analogs act as competitors of natural nucleosides triphosphate and compete with natural nucleosides (ATP, TTP, CTP, GTP) to participate in RNA transcription. When the gs-441524 molecule is inserted into the transcripts, the transcription will be terminated in advance, thus inhibiting the transcription process of viral RNA.
Bisulfite adduct gc376 is a broad-spectrum inhibitor, scientific name 3C protease inhibitor, which targets the 3C protease encoded by the virus.
Action mechanism of gc376
Based on the important role of 3C protease in virus replication. Blocking the cleavage of viral protease is an important entry point for the treatment of coronavirus infection.
Gc376 targets 3C protease and binds to the active site of 3C protease. During the reaction, gc376 lost the sulfite group structure and exposed the aldehyde group. The aldehyde group reacted with the nucleophilic cysteine residue (- Cys) of 3clpro to form a reversible covalent bond. It hinders the catalysis of 3CL like protease and then inhibits the replication of the virus.
How do viruses multiply？
After the genetic material (RNA, DNA) of the extracellular virus enters the host cell (i.e. normal cell of an organism) through the process of (a), it will use the adenosine triphosphate raw material in the host nucleus to copy and synthesize its own genetic material and the material conditions required for protein synthesis, such as messenger RNAThen, messenger RNA is used to synthesize its own protein (i.e. the (k) process in the figure) under the catalysis of various enzymes (such as 3C protease) in the host cell and the assistance of raw materials to form the shell. So far, the virus has completed reproduction. After the virus invades the host cell, it will replicate and synthesize many similar viruses, deplete the normal cell resources of the host until the normal cell is damaged and ruptured. However, the organism is composed of cells. If the cells are destroyed on a large scale, the organism will show pathological manifestations.
Discussion on clinical trials
Experiments show that gs-441524 is more effective than gc376 for naturally occurring FIP.
It is found that gs-441524 can reach the eyes and central nervous system through blood eye barrier and blood-brain barrier. Compared with the 20 cats treated with gc376, only 6 cats remained disease-free after more than 18 months. The therapeutic effect of gs-441524 is obviously more ideal, with less dose and shorter treatment cycle.
From the above, we can see that Gs-441524 acts on the replication stage of genetic material act as a competitor of natural nucleoside triphosphate and participates in the replication of cat coronavirus RNA. When a gs-441524 molecule is inserted into the viral RNA, the replication will fail, blocking the synthesis of cat coronavirus RNA from the source, and also affecting the synthesis of cat coronavirus shell protein later. It acts on stage (d) in the above figure.
Gc376 targets 3C protease and combine it with 3C protease to hinder the role of C protease in the synthesis of cat coronavirus coat protein. It can only act on the synthesis stage of coat protein, that is, the process (k) in the figure.
However, in general, the nucleoside analog gs-441524 still has great prospects in the treatment of naturally occurring FIP. It is hoped that this research result can be applied to the clinic as soon as possible and break through the barrier that FIP cannot treat. We will also pay close attention to the research trends and update them for you in time.