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Research progress of anti-influenza A virus peptide drugs

Flu is a seasonal acute respiratory disease characterized by high fever, runny nose, muscle aches and pains. Influenza viruses can be classified into A, B and C types ,Influenza A viruses (e.g. H1N1, H5N1) are the main pathogens causing influenza outbreaks in the world.Therefore, more attention has been paid to the study of influenza A virus.

Influenza A virus often undergo antigenic transformation and antigenic drift, resulting in its antigenic variation leading directly to the failure of human specific immunity.The best protection against influenza viruses is vaccination, but the vaccine has to be made repeatedly and in a cumbersome process ,It's effective but not used for long periods of time. Antiviral drugs have become an important means of preventing and treating influenza.

Currently, FDA-approved antiviral drugs for influenza include influenza virus M2 channel blockers (such as amantadine) and neuraminidase (NA) inhibitors (such as oseltamivir). The use of amantadine has been limited because the influenza virus has developed strong resistance to the M2 channel inhibitor.Although most influenza A viruses circulating remain sensitive to oseltamivir, oseltamivir-resistant strains have been isolated from human patients and animals. Therefore, there is an urgent need to develop a new security antiviral drugs to solve the emerging problem of influenza resistance in order to respond to future influenza pandemics.

In recent years, peptide drugs synthesized through related peptide synthesis technology have been successfully appear on the market for the treatment of pain, AIDS, irritable bowel syndrome and other diseases. As a drug, polypeptide has the advantages of high safety, good efficacy, selectivity and predictability in metabolism. With the continuous increase of influenza pandemic, antiviral peptide drugs have received extensive attention, and new antiviral peptide structure, mechanism of action and future treatment prospects are gradually presented to the public. Therefore, the research and development prospect of anti-influenza virus polypeptide drugs is very considerable

Influenza A virus peptide adsorption inhibitors block the binding of HA to receptors such as sialic acid on the surface of host cells by adding active peptides to competitively bind virus particles or host cells, thereby inhibiting the adsorption process of influenza virus. The advantage of such inhibitors is that they can cut off the transmission of the virus in the initial stage of infection, and minimize the damage of the virus to human body, thus providing a unique advantage in the prevention and treatment of influenza virus

The cell membrane destructor of influenza A virus produces antiviral activity through two mechanisms. One mechanism is that a cell membrane destructor with a large positive charge can produce electrostatic interactions with the virus, thereby punching in the membrane and killing the virus. The other mechanism is that the cell membrane breaker binds to the HA or NA proteins on the surface of the virus, thus destroying its function and realizing the inhibition of influenza virus infection. Because the electronegativity  of influenza virus cell membrane is weaker than the cell wall  ofbacteria , when the strong positive property of membrane destructor ACTS on influenza virus, it will show poor target selectivity.

Influenza A virus RNA polymerase contains PB1, PB2 and PA, and each of these subunits plays an indispensable role. In the polymerase trimer, PB1, as the skeleton, binds to the C terminal of PA through its N terminal, and the C terminal binds to the N terminal of PB2 to enable the polymerase to have functions. The replication inhibitor of  Influenza A virus is a polypeptide derived from the PB1 or PB2 subunits, Through the competitive combination of PB1, PB2 or PA to block the interaction between PB1 and PB2 or PB1 and PA, so as to interfere the aggregation of polymerase subunits, inhibit the activity of polymerase, and achieve the purpose of Resisting the spread of the flu virus.

Many highly flexible and selective anti-influenza peptide drugs have been found for the replication process of influenza A virus cell membrane and its adsorption with host cells and RNA , but there are still some potential problems need to be solved. Although peptide adsorption inhibitors can act on influenza A virus in the early stages of infection, their target HA proteins are prone to mutate, making them inactivated. Although peptide membrane destructors have high anti-influenza virus ability, most of them are antimicrobial peptides, which may produce cytotoxicity because of their weak selectivity against influenza viruses. Although the targets of peptide replication inhibitors are not easy to mutate, they exist in domain cells, so what they need to be solved is effectively cell delivery. In addition, a series of problems such as in vivo bioactivity of polypeptide , synthesis cost and the degree of protease degradation should be considered in the development of anti-influenza A peptide drugs.

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