Great potential for antiviral peptides against SARS-CoV-2

With the advent of a new, perhaps more pathogenic variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the 2019 coronavirus disease (COVID-19) pandemic may be far from over. not. With more than 3.7 million deaths recorded since the virus first appeared, the need for effective and safe antivirals has never been greater.

New research recently published in the journal Virus, Explains impressive evidence of the role of antimicrobial peptides (AMPs) in the treatment of COVID-19.

Background

SARS-CoV-2 infection is characterized by unpredictable symptoms. It is very often asymptomatic and causes symptoms in about 15% of cases.Unfortunately, it can cause rage Cytokine storm In about 5% of cases, lung damage and multiple organ dysfunction remain in its place as a result of dysregulated systemic inflammation.

Of the many drugs being developed for the treatment of COVID-19, none have proven to be clearly effective. Remdesivir only has the effect of slightly reducing hospital stays and does not affect mortality. Corticosteroids have powerful anti-inflammatory properties and reduce the risk of dying from severe COVID-19, but are double-edged weapons.

Hydroxychloroquine and azithromycin are claimed to have questionable evidence of efficacy, but most trials have serious flaws.

On the other hand, monoclonal antibody preparations are very expensive.

The virus itself mutates at a relatively high rate, and multiple variants are already prevalent. This means that resistance to antiviral drugs is likely to develop rapidly, indicating the need to develop new drugs.

Attractive AMP

AMP partially meets this bill with a wide range of activity against viruses and other pathogens. These positively charged peptides have amphipathic properties and can work properly.

These natural compounds are found in all higher organisms and many of them have significant antiviral activity. Synthetic AMPs designed to mimic native peptides can block important steps in viral activity. For example, inhibition of virus receptor binding, inhibition of virus adsorption, inhibition of protein-protein interaction, etc.

This is made possible by mimicking their structure to retain their biological function, but at the same time making them more powerful and selective. AMP has four different types of structures: linear α-helix peptides, β-sheet peptides, linearly elongated structures, and mixed α-helix and β-sheet peptides.

The AMP sequences are easy to manipulate and can be easily modified to overcome mutation resistance. The combination of AMP, or AMP with other drugs, can further reduce the risk of evading mutations, but it probably enhances antiviral activity through additive or synergistic effects. Finally, AMP often stimulates the innate immune response.

Defensin

One of the best examples of AMP is the defensin family. These were the first antiviral AMPs actually reported. In vitro Activity against herpes simplex virus (HSV) types 1 and 2 and cytomegalovirus (CMV). It was subsequently demonstrated to protect against SARS-CoV, human immunodeficiency virus (HIV), influenza A virus, human adenovirus, human papillomavirus (HPV), HSV, and respiratory syncytial virus (RSV).

These are β-sheet AMPs that can interact with anionic phospholipids to disrupt lipid membranes.Bind to Glycoprotein Or glycolipids; therefore, interact with viral proteins or receptors to inhibit viral infections.

The defensin-like peptide P9R has been shown to have potent antiviral activity against enveloped viruses that depend on acidic conditions for endosome entry into host cells. This includes not only highly pathogenic ones, but also Coronavirus, Influenza virus A H1N1pdm09 and H7N9.

Interestingly, P9R did not allow the development of resistance to the influenza virus even after 40 passages. Conversely, the approved drug, zanamivir, became ineffective because it gained resistance after only 10 passes in the presence of the virus.

It is derived from P9, which is derived from mouse β-defenssin 4, which has the same mechanism of action. The short P9 derivative binds to the HIV protein, introduces the defective influenza virus gene, and prevents endosome acidification.

Defensins successfully inhibit Zika virus and MERS-CoV and prevent viral invasion through a variety of mechanisms, including viral membrane disruption and inhibition of membrane fusion.

The first approved antiviral peptide was Enfuvirtide (T-20 or Fuzeon) for HIV.

AMP and SARS-CoV-2

Recently, another small molecule that mimics AMP, called brillacidin, has been shown to inhibit SARS-CoV-2 infection in vitro by blocking the entry of the virus into host cells. When combined with remdesivir, brillidin showed a synergistic effect.

Other AMPs, such as P9R and P9, block the early replication of SARS-CoV-2 because they inhibit endosome acidification. Mucroporin-M1 destroys the virus envelope. The human intestinal defensin 5 (HD5) resembles a natural lectin and prevents SARS-CoV-2-receptor binding by inhibiting SARS-CoV-2-receptor binding.

Some AMPs also help regulate the severity of COVID-19 due to their early effects on innate immunity.

Other AMP

Many other examples of AMP that block resistant influenza A virus strains, such as urumi from South Indian frogs, have been reported.

The Kα2 helix peptide, derived from another inhibitor protein, is active against the highly pathogenic H5N1 and H1N1 strains of influenza virus, destabilizes the viral membrane, and is resistant to RSV and vesicular stomatitis virus (VSV). It is also effective against it.

What is the future direction of AMP research?

Overall, the AMP database DRAMP has over 2,000 AMPs, providing a source of drug development. Among several mechanisms of virus suppression, the mechanism that prevents trafficking of the virus by inhibiting endosome acidification has special value for recently emerging highly pathogenic viruses.

It is relatively unlikely that AMP will cause a rapid development of tolerance. In addition, they can be modified quickly to overcome escape mutations. They have a high safety margin, as indicated by the Zika virus inhibitor Z2, which was non-toxic to pregnant mice and their foets.

They are also non-immunogenic. However, they have high production costs and short lifespans. These obstacles can be overcome, for example, by adopting optimized manufacturing methods that replace chemical synthesis with biosynthesis in the appropriate cell line expressing the recombinant peptide.

The researcher wrote:

Given the widespread and potent activity of AMP against multiple viruses, we recommend funding research into the development of AMP as a new therapeutic strategy for viral diseases.“