How Cyclodextrins work: 5 things we learned from Roquette

As the 2019-nCoV coronavirus sweeps across the globe, companies investigate 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. See what we learned from a recent paper by Roquette and learn how cyclodextrins can contribute to fighting the pandemic at hand.

Cyclodextrins as solubilizers help deliver drugs

Most often, hydroxypropyl beta-cyclodextrins (HPβCD) are used as solubilizers for the application of active pharmaceutical ingredients (APIs) to the mucous membranes of the nose, mouth and throat, among others. This 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

On top of their ability to effectively deliver APIs where they are needed, modified cyclodextrins act as effective broad-spectrum antivirals, as shown in a recent study published on Science Advances, Modified cyclodextrins as broad-spectrum antivirals:

“We have synthesized a biocompatible sulfonated CD that proved to be active against a large number of HS-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 2019-nCoV infection as there are currently no approved vaccines. Since the release of the 2019-nCoV genetic sequence in early January 2020, scientists have been working around the clock to produce stable versions of the vaccines, mainly based on non-living 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 (Th2) cell response, enhances antigen (vaccine)-specific antibody titers, and maintains longer immune response. As a result, HPβCD acts as a safe and efficient adjuvant in developing successful vaccines for 2019-nCoV prevention.

Cyclodextrins as excipients stabilize 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 maintain 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 as 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 are neither prevention nor cure for the 2019-nCoV infection, they can significantly contribute to the development of such measures. HPβCD can effectively act as an enabling excipient for solubility enhancement of antiviral drugs, 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.