Review of Part One: [R&D Status of Drugs Based on Influenza Pathogenesis (Part One)]
Drugs inhibiting influenza virus RNA polymerase
Influenza virus RNA polymerase is a protein complex composed of PA, PB1 and PB2 subunits. PA has endonuclease activity and can induce proteolysis. PB1 has RNA polymerase activity, and PB2 can recognize and bind to the host 5'mRNA cap structure, so as to play an important role in genome replication and transcription. At present, RNA polymerase inhibitors have become an important target for anti-influenza drug research because of their low mutation frequency and mild side effect.
1. Chemical drugs and small molecule compounds
Ribavirin, a guanosine ribonucleoside analogue, targets inosine 5' monophosphate dehydrogenase (IMPDH), which can inhibit viral RNA replication and induce RNA replication mutation by reducing the concentration of GTP in cells and preventing viral protein synthesis. Additionally, combined with glycyrrhizic acid, ribavirin can significantly reduce the expression levels of inflammatory factors IL-6, TNF-α and IL-1β. Pimodivir, which has entered Phase III clinical trials, targets PB2 subunit of RNA polymerase and inhibits the expression of virogene by preventing polymerase binding and cap structure of 7-methyl GTP in pre-mRNA host. And it also has activity against various kinds of influenza A viruses and strains with low sensitivity to NAIs. Baloxavir, which has been listed in the United States and Japan at present, targets the endonuclease activity of PA subunit virus. Once it is combined with PB2.8, it can prevent polymerase from cutting pre-mRNA, which is effective for influenza A, B viruses and even oseltamivir-resistant viruses. Favipiravir, a purine nucleoside analogue, is active against almost all influenza viruses. After ribosylation and phosphorylation in cells, it produces a drug-active form of nucleoside triphosphate fampiravir RTP. Viral RNA polymerase misrecognizes this form as purine and it is mistakenly incorporated into newborn RNA, which leads to chain termination in the process of RNA synthesis. In addition, it exerts anti-virus effects by inducing fatal mutation. Due to the outbreak of COVID-19 and other reasons, this drug has been listed in China.
2. Active ingredients of traditional Chinese medicine
Isoquercitrin can prevent virus replication and reduce the active methoxy group caused by influenza A infection through blocking the operation of PB2 in RNA polymerase. Silybin and silidianin, the main components of silymarin extracted from seeds of silybum marianum, can prevent virus from entering host cells, inhibit the formation of oxidative stress by regulating autophagy, and trigger extracellular signal regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) and inhibitor of nuclear factor kappa-B kinase (IKK) cascade. The binding affinity of toosendanin, the main active component of toosendan fruit, binding to PA is stronger than that of known PA inhibitors. Toosendanin destroys nuclear transport by changing the nuclear localization of PA protein, which leads to cytoplasm accumulation of PA and inhibits early replication of influenza virus mRNA. It can also interfere with virus entering host cells by inhibiting the activity of protein kinase B.
Drugs for relieving excessive body immunity
Anti-inflammatory immunity is an indispensible step for the body to fight against influenza virus. Inflammatory factors, as immune signal molecules, are released through NF-κB, Nrf2, JAK-STAT, RLRs, AMPK and other signaling pathways for self-defense. In addition to inhibiting the replication and spread of influenza virus, the excessive body immunity triggered by the transmission of inflammatory factors between immune cells should be blocked.
1. Chemical drugs and small molecule compounds
Intravenous immunoglobulin (IVIG) contains IgG antibody. It has dual therapeutic effects of immune substitution and immune regulation, which can reduce the mortality and morbidity related to severe influenza. IVIG is often used as the first-stage intervention measure in the influenza intensive care environment. Peroxisome proliferators-activated receptors γ (PP...
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