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How cyclodextrins work: Five things we learned from Roquette

A class of broad-spectrum antivirals, cyclodextrins have turned out to be a substance that could play a major role in fighting the pandemic at hand. (Images: CURADEN)


Tue. 5. May 2020


KRIENS, Switzerland: As the SARS-CoV-2 virus sweeps across the globe, companies are investigating potential agents that could help fight viruses. Cyclodextrins, broad-spectrum antivirals used to deliver active ingredients to the mucous membranes, seem to be among the top candidates. Roquette, a global company that specialises in providing plant-based ingredients for the food, nutrition and health markets, recently published a paper describing how cyclodextrins can contribute to fighting the current pandemic.

Cyclodextrins as solubilisers help deliver drugs

Most often, hydroxypropyl-beta-cyclodextrins (HPβCDs) are used as solubilisers for the application of active pharmaceutical ingredients to the mucous membranes of the nose, mouth, throat and other areas of the body. The use of solubilisers speeds up the development of antiviral drugs, as poor aqueous solubility of active compounds can often hamper and complicate the process of antiviral development.

Adequate drug solubility is imperative for ensuring bioavailability and, consequently, the efficacy of oral antiviral treatments. In the case of parenteral therapy, which offers the benefit of rapid onset in critically ill patients, drug solubility is even more critical, given that intravenous solutions must be particulate-free and buffered to physiological pH.

Cyclodextrins as antivirals actively fight viruses

In addition to their ability to effectively deliver active pharmaceutical ingredients where they are needed, modified cyclodextrins act as effective broad-spectrum antivirals, as shown in the recent study Modified cyclodextrins as broad-spectrum antivirals published in Science Advances.

The authors of this study concluded: “We have synthesised a biocompatible sulfonated CD [cyclodextrin] that proved to be active against a large number of HS-dependent [heparan sulphate-dependent] viruses. It exhibits a broad-spectrum virucidal, irreversible mechanism of action, presents a high barrier to viral resistance, and is biocompatible. We demonstrated its preventive and therapeutic activity both in cell lines and in human-derived pseudostratified and highly differentiated histocultures, mimicking faithfully the upper respiratory tract and the vagina as well as in a relevant murine model of HSV-2 infection. Modified CDs are thus potent tools to fight multiple viral infections.”

Cyclodextrins as adjuvants boost vaccine effects

Accelerated measures are being taken by companies and institutions to develop vaccines against SARS-CoV-2 infection, as there are currently no approved vaccines. Since the release of the SARS-CoV-2 genetic sequence in early January 2020, scientists have been working around the clock to produce stable versions of the vaccines, mainly based on subunit vaccine and mRNA vaccine technologies.

However, non-living vaccine antigens, especially subunit vaccines, are poorly immunogenic and require additional adjuvant components to stimulate immunity. As an adjuvant, HPβCD induces Type 2 T-helper cell response, enhances antigen antigen-specific antibody titres, and maintains longer immune response. As a result, HPβCD acts as a safe and efficient adjuvant in developing successful vaccines for COVID-19 prevention.

Cyclodextrins as excipients stabilise antibodies

Monoclonal antibodies can specifically target the virus and render long-term effects. However, since proteins are inherently unstable, the selection of appropriate excipients for final formulation is critical to maintaining antibody stability during storage and shipment.

Many case studies show that HPβCD is able to protect proteins from aggregation under various stress conditions. In addition, the validated safety profile in approved parenteral small-molecule drugs and the stability of HPβCD itself suggest it is a versatile excipient in antibody formulation development.

Cyclodextrins as membrane disruptors contain infection

Infection by enveloped viruses, including coronavirus and influenza virus, is mediated by viral binding to cellular receptors and the fusion of the viral envelope with the host cell membrane. Evidence suggests that cholesterol present in microdomains in the viral envelope and cell membrane are required for successful entry of enveloped viruses into the host cell.

Cyclodextrins are able to sequester cholesterol from viral particles, thereby causing lipid raft disruption and consequent structural deformation of the viral envelope. Cyclodextrins can also deplete cholesterol from host cell membranes, rendering them less susceptible to viral infection. In the form of prophylactic nasal and throat sprays, cyclodextrins can therefore prevent viral transmission via the respiratory route.

While cyclodextrins offer neither prevention nor cure for COVID-19, they can significantly contribute to the development of such measures. HPβCD can effectively act as an enabling excipient for solubility enhancement of antiviral drugs, for stability improvement of therapeutic monoclonal antibodies and as a vaccine adjuvant. Cyclodextrins can potentially be used for infection containment or as virucidal agents after structural modification.

The Roquette paper can be found under this link.

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