Periodic Reporting for period 3 - Fight-nCoV (FIGHTING-OFF CORONAVIRUS (SARS-CoV-2) WITH BROAD-SPECTRUM ANTIVIRALS: ESTABLISHING ANIMAL VIRAL CHALLENGE MODEL)
Okres sprawozdawczy: 2022-04-01 do 2022-09-30
The COVID-19 pandemic caused by the SARS-CoV-2 virus has affected millions of people globally and caused widespread economic and societal disruption. Despite the availability of vaccines, the emergence of new variants and the slow rate of vaccine rollout in some areas means that antiviral treatments remain a crucial tool in the fight against the virus. The development of antiviral treatments against SARS-CoV-2 is crucial for controlling the spread of the virus, reducing the severity of illness, and preventing hospitalizations and deaths. Antivirals can also play a pivotal role in treating individuals who cannot receive the vaccine, such as those with certain medical conditions or allergies. Additionally, antivirals can help to control outbreaks and slow the spread of the virus, reducing the strain on healthcare systems and allowing for a return to more normal social and economic activity.
The overall objectives of this project were the identification of new antivirals against SARS-CoV-2 and to test as well as optimize their efficacy. To this end, our consortium developed three different classes of so-called viral entry inhibitors and tested them in cell cultures as well as in several animal models. With this strategy, we hoped to find the most effective and safe compounds for the treatment of COVID-19, with the ultimate goal of improving outcomes for patients and controlling the spread of the virus.
The overall objectives of this project were the identification of new antivirals against SARS-CoV-2 and to test as well as optimize their efficacy. To this end, our consortium developed three different classes of so-called viral entry inhibitors and tested them in cell cultures as well as in several animal models. With this strategy, we hoped to find the most effective and safe compounds for the treatment of COVID-19, with the ultimate goal of improving outcomes for patients and controlling the spread of the virus.
The Fight-nCoV consortium was formed with the goal of developing new antiviral drugs to fight against SARS-CoV-2, the virus that causes COVID-19. Different classes of novel antivirals discovered in our laboratories were examined. For these compounds, a line of biological tests of increasing complexity was established, starting with laboratory tests, progressing to small animals, and finally to monkeys.
In the first phase of our collaborative project, a laboratory test was established, known as an in vitro screening assay, to evaluate the effectiveness of new antiviral drug candidates. The test was developed using different types of SARS-CoV-2 virus, such as Wuhan and variants of concern, as well as using different models in cell lines and primary lung epithelial cells. In these assays, we identified several molecules that turned out to be highly active and protective, even against other viral families.
Before entering animal tests (in vivo), the most active drug candidates were tested in mice to determine their level of toxicity and pharmacokinetic profiles. The second phase started with the development of a SARS-CoV-2 model in mice and hamsters.
Finally, a SARS-CoV-2 challenge model was established in small monkeys (non-human primates) that have a physiology much closer to human beings than mice or hamsters. The success of establishing a SARS-CoV-2 model in non-human primates was reported in the journal Nature in July 2020, just four months after the start of the program.
Based on all previous test results, two antiviral compounds, the molecular tweezer CP019 and a protease inhibitor were selected for the third test phase in macaques. To improve delivery in the respiratory tract, an aerosol process for drug administration was developed.
The Fight-nCoV project also evaluated an old antiviral drug, hydroxychloroquine. However, hydroxychloroquine did not show any effect against SARS-CoV-2 in non-human primate studies. By contrast, the molecular tweezer CP019 showed potential as an antiviral agent in several of the test animals, and is currently under further development and optimization, especially with respect to its improved formulation and dosing. We conclude that the development of an intranasal spray for the treatment of respiratory tract infections is possible.
Fight-nCoV partners have published 42 peer-review articles in open access and several in very high-impact journals. The partners have also actively participated in scientific meetings, workshops, TV, radio, and other media. Patent applications were submitted for two different classes of broad-spectrum antiviral compounds for further exploitation.
The clinical feasibility and development plans were evaluated and it can be concluded that the development of an intranasal spray for the treatment of respiratory tract infections is feasible. It is conceivable that the development of a broad-spectrum antiviral to be used to curb a pandemic threat is initially developed for the treatment of one respiratory tract infection with a recurrent epidemic occurrence and medical need that at the same time can be evaluated in a viral challenge model of healthy adult volunteers who does not risk getting a severe disease (examples RSV and influenza). The license and building production capacities as well as marketing for a broad-spectrum antiviral to treat one virus infection will facilitate the extension of treatment indications to other virus infections and enables kick-starting of new clinical trials when required. Altogether, the Fight-nCoV project has identified new broad-spectrum antivirals that have the potential to be developed further for clinical use.
In the first phase of our collaborative project, a laboratory test was established, known as an in vitro screening assay, to evaluate the effectiveness of new antiviral drug candidates. The test was developed using different types of SARS-CoV-2 virus, such as Wuhan and variants of concern, as well as using different models in cell lines and primary lung epithelial cells. In these assays, we identified several molecules that turned out to be highly active and protective, even against other viral families.
Before entering animal tests (in vivo), the most active drug candidates were tested in mice to determine their level of toxicity and pharmacokinetic profiles. The second phase started with the development of a SARS-CoV-2 model in mice and hamsters.
Finally, a SARS-CoV-2 challenge model was established in small monkeys (non-human primates) that have a physiology much closer to human beings than mice or hamsters. The success of establishing a SARS-CoV-2 model in non-human primates was reported in the journal Nature in July 2020, just four months after the start of the program.
Based on all previous test results, two antiviral compounds, the molecular tweezer CP019 and a protease inhibitor were selected for the third test phase in macaques. To improve delivery in the respiratory tract, an aerosol process for drug administration was developed.
The Fight-nCoV project also evaluated an old antiviral drug, hydroxychloroquine. However, hydroxychloroquine did not show any effect against SARS-CoV-2 in non-human primate studies. By contrast, the molecular tweezer CP019 showed potential as an antiviral agent in several of the test animals, and is currently under further development and optimization, especially with respect to its improved formulation and dosing. We conclude that the development of an intranasal spray for the treatment of respiratory tract infections is possible.
Fight-nCoV partners have published 42 peer-review articles in open access and several in very high-impact journals. The partners have also actively participated in scientific meetings, workshops, TV, radio, and other media. Patent applications were submitted for two different classes of broad-spectrum antiviral compounds for further exploitation.
The clinical feasibility and development plans were evaluated and it can be concluded that the development of an intranasal spray for the treatment of respiratory tract infections is feasible. It is conceivable that the development of a broad-spectrum antiviral to be used to curb a pandemic threat is initially developed for the treatment of one respiratory tract infection with a recurrent epidemic occurrence and medical need that at the same time can be evaluated in a viral challenge model of healthy adult volunteers who does not risk getting a severe disease (examples RSV and influenza). The license and building production capacities as well as marketing for a broad-spectrum antiviral to treat one virus infection will facilitate the extension of treatment indications to other virus infections and enables kick-starting of new clinical trials when required. Altogether, the Fight-nCoV project has identified new broad-spectrum antivirals that have the potential to be developed further for clinical use.
First, we have contributed to public health preparedness and responded to the ongoing epidemic of SARS-CoV-2 by building capacity allowing the testing of new antiviral treatments in different cell types.
Second, a central core of this project was to build capacity for SARS-CoV-2 non-human challenge experiments. This core objective significantly enhanced innovation capacity specifically to combat SARS-CoV-2.
The third objective was to evaluate different broad-spectrum antivirals to be given intranasally/inhalation. There is a huge unmet need to develop novel ways to combat not only SARS-CoV-2 but also other respiratory tract infections such as RSV and Influenza A. In addition, there is always the constant threat of new viral transmission from animals to human beings. We have identified lead compounds with potent broad-spectrum anti-viral activity and provided the first proof-of-concept of anti-viral effectiveness.
Molecular tweezers are unique because they introduce an entirely new mechanism of action: Each tweezer molecule encapsulates a lipid head group inside the viral membrane and greatly enhances the surface tension. Membrane rupture eventually leads to a complete loss of infectivity. This universal mechanism works on all enveloped viruses including newly emerging species. Our tweezers thus possess a broad antiviral potential that may be rapidly used against the threat of future pandemics.
The Fight-nCoV consortium has recognized that dissemination activities to the different groups of stakeholders are an essential activity throughout the project´s life and beyond to promote the project and its specific outcomes as well as further exploitation of results. The regular exchange between the different stakeholders and the consortium facilitated the successful implementation of the project and also increased the innovation potential.
Key messages
• Broad-spectrum antivirals are an important complement to vaccines as these can be stored on the shelf and be ready for use early during a pandemic threat.
• Our broad-spectrum antivirals have the prospects of being useful against recurrent epidemics such as SARS-CoV-2, influenza, and RSV, and based on the broad antiviral activity, against newly emerging enveloped viral pathogens.
Second, a central core of this project was to build capacity for SARS-CoV-2 non-human challenge experiments. This core objective significantly enhanced innovation capacity specifically to combat SARS-CoV-2.
The third objective was to evaluate different broad-spectrum antivirals to be given intranasally/inhalation. There is a huge unmet need to develop novel ways to combat not only SARS-CoV-2 but also other respiratory tract infections such as RSV and Influenza A. In addition, there is always the constant threat of new viral transmission from animals to human beings. We have identified lead compounds with potent broad-spectrum anti-viral activity and provided the first proof-of-concept of anti-viral effectiveness.
Molecular tweezers are unique because they introduce an entirely new mechanism of action: Each tweezer molecule encapsulates a lipid head group inside the viral membrane and greatly enhances the surface tension. Membrane rupture eventually leads to a complete loss of infectivity. This universal mechanism works on all enveloped viruses including newly emerging species. Our tweezers thus possess a broad antiviral potential that may be rapidly used against the threat of future pandemics.
The Fight-nCoV consortium has recognized that dissemination activities to the different groups of stakeholders are an essential activity throughout the project´s life and beyond to promote the project and its specific outcomes as well as further exploitation of results. The regular exchange between the different stakeholders and the consortium facilitated the successful implementation of the project and also increased the innovation potential.
Key messages
• Broad-spectrum antivirals are an important complement to vaccines as these can be stored on the shelf and be ready for use early during a pandemic threat.
• Our broad-spectrum antivirals have the prospects of being useful against recurrent epidemics such as SARS-CoV-2, influenza, and RSV, and based on the broad antiviral activity, against newly emerging enveloped viral pathogens.