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Medchem & Toxicology 2018
Page 76
Journal of Organic & Inorganic Chemistry
ISSN: 2472-1123
A n n u a l C o n g r e s s o n
Medicinal Chemistry,
Pharmacology and toxicology
J u l y 3 0 - 3 1 , 2 0 1 8
Am s t e r d a m , N e t h e r l a n d s
P
harmacological therapy with small molecules is a transversal approach and can be applied when instability of a protein is the
first cause of pathology. Small molecules can act by direct interaction with the affected protein, and in this case are defined
pharmacological chaperones or stabilizing mutants indirectly. A large proportion of Fabry mutations destabilize lysosomal
α-galactosidase (AGAL). A pharmacological chaperone, 1-deoxygalactonojirimycin, is already in clinical trial. In order to test the
effects of drugs on different mutations, a cell based assay has been developed. Expression vectors encoding mutant AGAL are
transiently transfected into mammalian cells and the residual activity of the enzyme is measured in the extracts of cells that had
been treated or not treated with the drug. These data offer the unique possibility of associating a numerical value that correlates
to the severity of the damage to hundreds of mutations. 1-deoxygalactonojirimycin is a promising drug, but, regrettably, it is
an inhibitor of the enzyme. The therapy needs a precise regimen to balance the stabilizing effect of the drug, which is required,
versus the inhibitory effect, which is detrimental. Allosteric ligands might act as pharmacological chaperones, and in this case
they might prove to be more effective than reversible inhibitors, since they would play their stabilising action without competing
with the natural substrate. A pilot study of our laboratory demonstrated that non inhibitory small molecules can be found for Fabry
disease.
cubellis@unina.itAn integrated approach to tackle Fabry disease
Maria Vittoria Cubellis
1
, Chiara Cimmaruta
1
, Valentina Citro
1
,
Bruno Hay-Mele
1
, Ludovica Liguori
2
and Giuseppina Andreotti
3
1
Università Federico II, Napoli, Italia
2
Dipartimento di scienze e tecnologie ambientali, biologiche e farmaceutiche, Università della
Campania Luigi Vanvitelli, Caserta, Italia
3
ICB- Consiglio Nazionale delle Ricerche. Pozzuoli, Italia
J Org Inorg Chem 2018, Volume 4
DOI: 10.21767/2472-1123-C3-009