PADCOV - Preventative Action for Safe and Fast Deactivation of COVID-19

The PROBLEM:

Due to the rapid outbreak of novel coronavirus and pandemic which affects the whole world, the current need for effective sanitizing agents is extreme. The global hand sanitizer market is valued almost $3 billion and expected to increase by 40% in the following years according to some open-access market analysis reaching $5.5 Billion by 2024. In March 2020, Unilever Company announced that they are boosting production capacity of hand sanitizers to meet the customer demand amid outbreak of Covid-19 (“Hand Sanitizer Market Anticipated to Reach $5.5 Billion in 2024 - ReportsnReports - Bloomberg,” n.d.). The main problem with conventional sanitizers is that they do not adequately prevent infection and transfer of viruses, including COVID19: mechanisms of action are too long and do not exhibit activity for an extended time once exposed to the environment. Alcohol-based hand sanitizers evaporate quickly (The flash points of ethanol 80% is 17.5°C) and cause skin irritations, chlorine-based are corrosive and polluting (“WHO | Alcohol-Based Handrub Risks/Hazards,” n.d.).

Because of this, preventative treatments are not effectively inhibiting the virus or stopping transfer of infection between hosts.

The NOVEL SOLUTION:

Development of non-toxic, biocompatible synergistic core-shell nanoparticles which are stable in alcoholic solutions and after being exposed to the environment. The novel particles are of matching size to the centre-to-centre spike distance on the target virus. The proposed nanocomposite is based on natural compounds and does not exhibit toxicity towards human cells and is eco-friendly.

For a theoretical proof of concept, see below in supplementary information. The specific study (http://doi.org/10.20944/preprints202003.02777.v1) supports our theory for a novel nanocomposite antiviral agent.

Solutions IMPACT immediately and AFTER THE CRISIS:

As an interdisciplinary group, we screened and mapped relevant literature and developed the theory for a new preventative antiviral agent. By the end of the Hack-a-thon we have a fully researched idea for a novel antiviral agent against COVID-19. Our topical agent will not only be applicable in the current pandemic climate but will be a useful sanitizing alternative to other pathogens (including resistant strains) beyond COVID-19.

NECESSITIES for further progress:

We are a dedicated research and development team who are able to carry out proof of concept and further develop our proposed technology. We will, however, require input from expert consultants to aid progress of the project. We will also need access to a type three biological laboratory to test our developed prototype. Ultimately we require financial support as well as scientific advice from field experts.

Contribution:

Team Leader - Giada Caniglia Literature Search - Verdiana Marchianò, Ekaterina Kukushkina, Diellza Bajrami, Nazan Altun Technical Assistance - Catarina Duarte, Agustina Sarquis, Miren Ruiz de Eguilaz Pajuelo, Shayesteh Bazsefidpar, Syed Imdadul Hossain Spokesperson (Presenter) - Ellie Stepaniuk Scribe - All together Illustrations - Maksim Drozdov

Supplementary Information (research to support our proposal):

Structural features of COVID19 (keywords, highlighted in blue what should be present in PPT):

It has been reported that the virion diameter ranges from 60 to 140 nm (Cascella et al., 2020). The spikes of COVID19 are responsible for the rapid interaction and penetration inside the host cell and they contain S proteins (Ibrahim et al., 2020). Taking into account center-to-center distance between the spikes which has an average of 10-30 nm (Neuman et al., 2006), we can assume that physical obstacles could be introduced in a way that spikes will be less flexible and blocked by presence of nanoparticles. The size of nanoparticles could be tuned and matched in a way that it will provide the most efficient size-dependent nanoparticle-virion interaction.

Examples of anchoring of the virion particle prevention: There are examples of core-shell nanostructures in the literature present which show the possibility to bind glycoproteins of the spikes of other virions to the surface of ultrafine nanoparticles in size-dependent manner (Orłowski et al., 2018). Blocking virus attachment by creating biological affinity for viral glycoproteins, simultaneously enhancing the action by encapsulation antiviral agent. So the main and the most important action: interaction with the virus surface, in particular the spike, through chemical compound moieties and creation of sterical barriers leading to immobilization of the virus and subsequent death.

Nanoparticles structure:

1) Shell

The first example of nanoparticle-virion interaction which was already mentioned is providing the mechanism and detailed description of tannic acid and other tannins being able to target viral glycoprotein (Lin et al., 2011). The antimicrobial activity, in particular antiviral action mode, is described by the ability of these natural compounds to block interaction between glycosaminoglycans (GAGs) of the host with glycoproteins of the virion. In fact, a screening of a library of hydrolyzable tannins and the possibility to bind with the Catalytic-Closed Sites of COVID-19 Main Protease and it has been proven that this approach has a potential (Khalifa et al., 2020). (Another options: to use a PLGA shell as a carrier, but with pretreatment: addition of the antiviral compound on the surface of the polymer which has affinity to the proteins of the spikes; to use functionalized chitosan, which also gives a great example of potential shell).

2) Core

The core will be formed by “green” drugs with antiviral activity as curcumin or capsaicin to reduce side effects and cost-effective. Curcumin blocks the virus entrance in the host cell, so its penetration and viral replicative cycle (Mathew et al., 2018). Capsaicin is a conventional antimicrobial agent which is able to which in theory inhibits replication cycle of the virion (Zorofchian Moghadamtousi et al., 2014). Functionalized carbon dot as potential antiviral agent also might be used as a core (Łoczechin et al., 2019). The release of the core should be considered according to the spike activity towards the shell. (These natural compounds are able to inhibit the viral replication cycle in the case of virion penetrating inside the host cells (but it still carries our nanoparticles in between spikes).)

3) Encapsulation examples

There are some studies that confirm the possibility to synthesize nanoparticles formed by a polymeric or polyphenolic shell able to encapsulate drugs. Polymeric nanoparticles can have a suitable size for our target, especially using PLGA and PEG. For example in this article the size is 40 nm and two drugs have been encapsulated: “Preparation and characterization of PLGA-PEG-PLGA polymeric nanoparticles for co-delivery of 5-Fluorouracil and Chrysin” ( Khaledi, S. et al., 2020).

The shell of this nanoparticles can be functionalized with amino-chitosan for its different biological activities, a study evidences its ability to have an antiviral effect and its low solubility can be solved modifying its functional groups. At the end it can also be used as a drug for the encapsulation. “The improved antiviral activities of amino-modified chitosan derivatives on Newcastle virus” ( He, Xiaofei et al., 2019) . Recent studies confirmed the antiviral activity of tannins and tannic acid, they can be used to stabilize the formulation ( emulsion or nanoparticles suspension) and allow the release of the drug. “Tannic Acid Modified Silver Nanoparticles Show Antiviral Activity in Herpes Simplex Virus Type 2 Infection” (Piotr Orlowski et al., 2014).

References

Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S.C., Di Napoli, R., 2020. Features, Evaluation and Treatment Coronavirus (COVID-19), in: StatPearls. StatPearls Publishing, Treasure Island (FL). Hand Sanitizer Market Anticipated to Reach $5.5 Billion in 2024 - ReportsnReports - Bloomberg [WWW Document], n.d. URL https://www.bloomberg.com/press-releases/2020-03-27/hand-sanitizer-market-anticipated-to-reach-5-5-billion-in-2024-reportsnreports (accessed 4.26.20). Ibrahim, I.M., Abdelmalek, D.H., Elshahat, M.E., Elfiky, A.A., 2020. COVID-19 spike-host cell receptor GRP78 binding site prediction. J. Infect. 80, 554–562. https://doi.org/10.1016/j.jinf.2020.02.026 Khalifa, I., Zhu, W., Nafie, M.S., Dutta, K., Li, C., 2020. Anti-COVID-19 Effects of Ten Structurally Different Hydrolysable Tannins through Binding with the Catalytic-Closed Sites of COVID-19 Main Protease: An In-Silico Approach. https://doi.org/10.20944/preprints202003.0277.v1 Lin, L.-T., Chen, T.-Y., Chung, C.-Y., Noyce, R.S., Grindley, T.B., McCormick, C., Lin, T.-C., Wang, G.-H., Lin, C.-C., Richardson, C.D., 2011. Hydrolyzable tannins (chebulagic acid and punicalagin) target viral glycoprotein-glycosaminoglycan interactions to inhibit herpes simplex virus 1 entry and cell-to-cell spread. J. Virol. 85, 4386–4398. https://doi.org/10.1128/JVI.01492-10 Łoczechin, A., Séron, K., Barras, A., Giovanelli, E., Belouzard, S., Chen, Y.-T., Metzler-Nolte, N., Boukherroub, R., Dubuisson, J., Szunerits, S., 2019. Functional Carbon Quantum Dots as Medical Countermeasures to Human Coronavirus. ACS Appl. Mater. Interfaces 11, 42964–42974. https://doi.org/10.1021/acsami.9b15032 Neuman, B.W., Adair, B.D., Yoshioka, C., Quispe, J.D., Orca, G., Kuhn, P., Milligan, R.A., Yeager, M., Buchmeier, M.J., 2006. Supramolecular Architecture of Severe Acute Respiratory Syndrome Coronavirus Revealed by Electron Cryomicroscopy. J. Virol. 80, 7918–7928. https://doi.org/10.1128/JVI.00645-06 Orłowski, P., Kowalczyk, A., Tomaszewska, E., Ranoszek-Soliwoda, K., Węgrzyn, A., Grzesiak, J., Celichowski, G., Grobelny, J., Eriksson, K., Krzyzowska, M., 2018. Antiviral Activity of Tannic Acid Modified Silver Nanoparticles: Potential to Activate Immune Response in Herpes Genitalis. Viruses 10. https://doi.org/10.3390/v10100524 WHO | Alcohol-Based Handrub Risks/Hazards [WWW Document], n.d. . WHO. URL https://www.who.int/gpsc/tools/faqs/abhr2/en/ (accessed 4.26.20). Zorofchian Moghadamtousi, S., Abdul Kadir, H., Hassandarvish, P., Tajik, H., Abubakar, S., Zandi, K., 2014. A Review on Antibacterial, Antiviral, and Antifungal Activity of Curcumin. BioMed Res. Int. 2014. https://doi.org/10.1155/2014/186864

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