Interactions between cyclodextrins and cellular components: Towards greener medical applications?

Leclercq, Loïc

The potential occurrence of synergistic effects presents a special case, and may occur when one substance increases the activity of another. Currently, gaps in our knowledge of the circumstances under which such effects may occur (e.g., mixture composition, contact time, species, and exposure concentrations) often hamper predictive approaches. However, since the CDs are able to extract cholesterol and other lipids from the viral membrane, it is likely that their combination with virucides or antiviral drugs which act on the same target results in a synergistic effect. Based on this assumption, our group studied the combination of di-n-decyldimethylammonium chloride, [DiC 10 ][Cl] (the most widely used cationic surfactant with intrinsic virucidal activity), and native CDs (α-, β-and γ-CD) [159] . A marked synergism was observed with γ-CD against lipid-containing deoxyribonucleic and ribonucleic acid viruses (HSV-1, respiratory syncytial virus, RSV), and vaccinia viruses, VACV). Indeed, noticeable reductions of the [DiC 10 ][Cl] concentration (i.e., active virucide) were obtained: 72, 40 and 85% against HSV-1, RSV and VACV, respectively. In all cases, submillimolar [DiC 10 ][Cl] and γ-CD concentrations were re-quired to obtain a "6-log reduction" (equivalent to 99.9999% reduction) of the viral titer. Therefore, for these diluted solutions, free CD and [DiC 10 ] species prevail due to the Le Châtelier's principle. Moreover, the micellization equilibrium is not relevant as the virucidal activity was clearly obtained in the premicellar region. Thus, the proposed mechanism of the synergy is based on the ability of CD to extract rapidly cholesterol from the viral envelope. Indeed, γ-CD catalyzes the rapid exchange of cholesterol between the viral envelope and the aqueous solution. The sequestration of cholesterol in the bulk phase facilitates the [DiC 10 ] insertion within the lipid envelope which leads to the virus inactivation (Scheme 7). This means that γ-CD accelerates the rate of cholesterol extraction by a larger factor than α-or β-CD. The proposed mechanism is highly compatible with the results of Leventis and Silvius (see above) [60] . These results demonstrate a clear effect of CDs on the "viability" of enveloped viruses and provide evidences of their potential use in order to improve the efficiency of common antiviral medications.