Rescuing compound bioactivity in a secondary cell-based screening by using gamma-cyclodextrin as a molecular carrier

Claveria-Gimeno, R. ; Vega, S. ; Grazu, V. (Universidad de Zaragoza) ; de la Fuente, J.M. (Universidad de Zaragoza) ; Lanas, A. (Universidad de Zaragoza) ; Velazquez-Campoy, A. (Universidad de Zaragoza) ; Abian, O.

Resumen: In vitro primary screening for identifying bioactive compounds (inhibitors, activators or pharmacological chaperones) against a protein target results in the discovery of lead com- pounds that must be tested in cell-based efficacy secondary screenings. Very often lead com- pounds do not succeed because of an apparent low potency in cell assays, despite an excellent performance in primary screening. Primary and secondary screenings differ significantly accord- ing to the conditions and challenges the compounds must overcome in order to interact with their intended target. Cellular internalization and intracellular metabolism are some of the difficulties the compounds must confront and different strategies can be envisaged for minimizing that prob- lem. Using a novel screening procedure we have identified 15 compounds inhibiting the hepatitis C NS3 protease in an allosteric fashion. After characterizing biophysically the interaction with the target, some of the compounds were not able to inhibit viral replication in cell assays. In order to overcome this obstacle and potentially improve cellular internalization three of these compounds were complexed with gamma-cyclodextrin. Two of them showed a five- and 16-fold activity increase, compared to their activity when delivered as free compounds in solution (while gamma-cyclodextrin did not show antiviral activity by itself ). The most remarkable result came from a third compound that showed no antiviral activity in cell assays when delivered free in solu- tion, but its gamma-cyclodextrin complex exhibited a 50% effective concentration of 5 micromoles. Thus, the antiviral activity of these compounds can be significantly improved, even completely rescued, using gamma-cyclodextrin as carrier molecule.

Idioma: Inglés

DOI: 10.2147/IJN.S79480

Año: 2015

Publicado en: International Journal of Nanomedicine 10 (2015), 2249-2259
ISSN: 1176-9114

Factor impacto JCR: 4.32 (2015)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 40 / 255 = 0.157 (2015) - Q1 - T1
Categ. JCR: NANOSCIENCE & NANOTECHNOLOGY rank: 26 / 83 = 0.313 (2015) - Q2 - T1

Factor impacto SCIMAGO: 1.323 - Bioengineering (Q1) - Biomaterials (Q1) - Biophysics (Q1) - Organic Chemistry (Q1) - Medicine (miscellaneous) (Q1) - Nanoscience and Nanotechnology (Q1) - Drug Discovery (Q1)

Financiación: info:eu-repo/grantAgreement/ES/FIS/PI10-00186
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI11-02578
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CP07-00289
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19451
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PTA2009-2341-I
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)