Cyclodextrins in Antiviral Therapeutics and Vaccines

Abstract

The present review describes the various roles of cyclodextrins (CDs) in vaccines against viruses and in antiviral therapeutics. The first section describes the most commonly studied application of cyclodextrins-solubilisation and stabilisation of antiviral drugs; some examples also refer to their beneficial taste-masking activity. The second part of the review describes the role of cyclodextrins in antiviral vaccine development and stabilisation, where they are employed as adjuvants and cryopreserving agents. In addition, cyclodextrin-based polymers as delivery systems for mRNA are currently under development. Lastly, the use of cyclodextrins as pharmaceutical active ingredients for the treatment of viral infections is explored. This new field of application is still taking its first steps. Nevertheless, promising results from the use of cyclodextrins as agents to treat other pathologies are encouraging. We present potential applications of the results reported in the literature and highlight the products that are already available on the market.

Keywords: antiviral drugs; cyclodextrins; inclusion complexes; vaccines.

Figure 1

The three most abundant native cyclodextrins (CDs), α-CD, β-CD, and γ-CD, schematically drawn as truncated cones. An estimate of the inner cavity diameter is presented for each [20].

Figure 2

Structural representation of β-CD and three of its derivatives: (2-hydroxy)propyl-beta-cyclodextrin (HPβCD), randomly methylated beta-cyclodextrin (RAMEB), and sulfobutyl ether β-CD (SBEβCD). The main skeleton of β-CD is represented in blue and the substituent groups are highlighted with different colours (carbon in grey, oxygen in red, hydrogen in white, sulphur in yellow and sodium in purple).

Figure 3

Commercially available antiviral active pharmaceutical ingredients (APIs) reported to form inclusion complexes and/or interaction products with native and chemically modified cyclodextrins.

Figure 4

Comparison of the solubility isotherms of efavirenz (EFV) with different cyclodextrins. Adapted from literature reports on EFV with β-CD and RAMEB [56]; γ-CD and HPγCD [54].

Figure 5

Structural representation of the interaction between remdesivir (molecules highlighted in green) and SBEβCD, as evaluated by molecular dynamics. Reproduced with permission from [86].

Figure 6

Schematic representation of the interactions between adenovirus particles (orange) and HPβCD molecules (blue) in the ad26.cov2.s vaccine. Cyclodextrin molecules are used in large excess and claimed to act as cryopreservatives, helping to stabilise the surface of the virus during the freeze-drying step of the vaccine preparation.

Figure 7

Schematic depiction of the biomolecular targets of HPβCD-mediated immunogenicity in mice [95].

Figure 8

Structural representation of the cyclodextrin–polyethyleneimine conjugated polymer; the ratio of cyclodextrin residues in the polymer can be tuned by varying the length at the m1 and m2 subunits.