With the emergence of new and possibly more pathogenic variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic of coronavirus disease 2019 (COVID-19) may be far from over. And with over 3.7 million deaths recorded since the virus first emerged, the need for effective and safe antivirals has never been greater.
A new study, recently published in the journal Viruses, describes the impressive evidence for the role of antimicrobial peptidse (AMPs) in the treatment of COVID-19.
Background
SARS-CoV-2 infection is characterized by its unpredictable symptomatology. Asymptomatic in a very large percentage of cases, it causes symptoms in about 15% of cases. Unfortunately, it can induce a raging cytokine storm in about 5% of cases, leaving lung damage and multi-organ dysfunction in its trail as a result of dysregulated systemic inflammation.
Among the many drugs that have been deployed for the treatment of COVID-19, none have proved unequivocally effective. Remdesivir is effective only in reducing the duration of hospitalization slightly, but has no impact on mortality. Corticosteroids have potent anti-inflammatory activity, and do reduce the risk of death in severe COVID-19, but are a double-edged weapon.
Hydroxychloroquine and azithromycin are claimed to have doubtful evidence of efficacy, though most trials have been seriously flawed.
Monoclonal antibody formulations, meanwhile, are very expensive.
The virus itself mutates at a relatively rapid rate, and multiple variants are already circulating. This means that resistance to antiviral drugs is likely to emerge rapidly, indicating the need for new and novel drugs to be developed.
Attractive AMPs
AMPs fill this bill, in part, with a broad spectrum of activity against viruses as well as other pathogens. These positively charged peptides have amphipathic properties, which allow them to do their job properly.
These natural compounds are found in all higher organisms, and many of them have significant antiviral activity. Synthetic AMPs designed to mimic natural peptides can inhibit essential steps in viral activity, such as inhibiting virus-receptor binding, blocking viral adsorption, or inhibiting protein-protein interactions, for instance.
This is possible by imitating their structure to retain their biological function, but simultaneously making them more potent and selective. AMPs have four different types of structure, namely, linear α-helical peptides, β-sheet peptides, linear extension structures, and mixed α-helix and β-sheet peptides.
AMP sequences are easily engineered, making it easy to modify them to overcome mutational resistance. The use of a combination of AMPs, or AMPs with other drugs, can further reduce the risk of escape mutants, while perhaps enhancing antiviral activity by additive or synergistic effects. Finally, AMPs often stimulate the innate immune response
Defensins
One excellent example of AMPs is the defensin family. These were the first antiviral AMPs to be reported, in fact, with in vitro activity against herpes simplex virus (HSV) types 1 and 2 and cytomegalovirus (CMV). Later, they have proved 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 which can interact with anionic phospholipids to break up lipid membranes; bind to glycoprotein or glycolipids; and thus interact with viral proteins or receptors to inhibit viral infection.
The defensin-like peptide P9R has been shown to have potent antiviral activity against enveloped viruses that depend on acidic conditions for endosomal entry into the host cells. This includes not only the highly pathogenic coronaviruses, the influenza viruses A H1N1pdm09 and H7N9.
Interestingly, P9R did not allow resistance to emerge in the influenza virus even after 40 passages. Conversely, the approved drug zanamivir became ineffective after the virus was passaged just 10 times in its presence, due to the acquisition of resistance.
It was derived from P9, which in turn comes from the mouse β-defensin 4, which shows the same mechanism of action. Short P9 derivatives have been conjugated to an HIV protein, introducing defective influenza virus genes, and thus preventing endosomal acidification.
Defensins have successfully inhibited Zika virus and MERS-CoV through different mechanisms, such as disrupting the viral membrane or inhibiting membrane fusion and thus viral entry.
The first antiviral peptide to be approved was Enfuvirtide (T-20 or Fuzeon) against HIV.
AMPs and SARS-CoV-2
Recently, another small molecule mimicking an AMP, called Brilacidin, was shown to inhibit SARS-CoV-2 infection in vitro by blocking viral entry into the host cell. In combination with remdesivir, Brilacidin had synergistic activity.
Other AMPs like P9R or P9 inhibit endosomal acidification, and thus block the early replication of SARS-CoV-2. Mucroporin-M1 disrupts the viral envelope. Human intestinal defensin 5 (HD5) is similar to a natural lectin, preventing SARS-CoV-2-receptor binding by blocking the latter.
Some AMPs also help modulate the severity of COVID-19 by their effect on early innate immunity.
Other AMPs
Many other examples of AMPs have been reported, such as urumin, from a South Indian frog, which inhibits resistant influenza A virus strains.
The Kα2-helix peptide from another inhibitor protein is active against highly pathogenic H5N1 and H1N1 strains of the influenza virus, destabilizing viral membranes, as well as RSV and vesicular stomatitis virus (VSV).
What are the future directions for AMP research?
Overall, there are over 2,000 AMPs on the AMP database DRAMP, providing a source for drug development. Among the several mechanisms of viral inhibition, those that prevent viral trafficking by inhibiting endosomal acidification are of special value against the highly pathogenic viruses of recent origin.
AMPs are relatively unlikely to trigger the rapid development of resistance. Moreover, they can be rapidly modified to overcome escape mutations. They have a high safety margin, as illustrated by the Zika virus inhibitor Z2, which was non-toxic to pregnant mice and their fetuses.
They are also non-immunogenic. However, they are more costly to produce, and short-lived. These hindrances can be overcome, for example, by adopting optimized manufacturing practices, where chemical synthesis is substituted with biosynthesis in appropriate cell lines, expressing recombinant peptides.
The researchers write:
Given the broad and potent activities of AMPs against multiple viruses, we recommend the funding of research into the development of AMPs as a new therapeutic strategy against viral diseases.”
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