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Synthesis and evaluation of glucosidase inhibitors with potential anti-HIV activity

Grant number: 07/00910-6
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2008
Effective date (End): August 31, 2011
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Ivone Carvalho
Grantee:Valquiria Aragão Leoneti
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Glucosidases are enzymes that catalyze the cleavage of glycosidic bonds in oligosaccharides or glycoconjugates. Several glucosidases are specific for the cleavage of glycosidic bonds depending on the number, position or configuration of the hydroxyl groups in the sugar molecule. The activity of glucosidases is fundamental to several biochemical processes such as (i) degradation of diet polysaccharides to furnish monosaccharide units which are then able to be metabolically absorbed and used by the organism, (ii) lysosomal glycoconjugate catabolism and glycoprotein processing, and (iii) biosynthesis of oligosaccharide units in glycoproteins or glycolipids.Inhibitors of glucosidase I and II have also been studied as potential anti-HIV agents. The HIV viral envelope is composed of a bilipidic layer and a complex protein known as env that consists of glycoproteins gp41 (transmembrane) and gp120, the latter being displayed on the viral surface and anchored to gp41. Glucosidases I and II participate in the formation of gp120, through the processing of the Glc3Man9GlcNAc2 N-linked glycoprotein, which is responsible for the recognition of the virus by CD4 receptors from T4 lymphocytes, in the initial process of viral infection. The modulation of the antigenicity of gp120 is dependent on the extension and variability of surface glycosylation and represents an interesting target to be explored in drug design.Iminosugars, isolated from plants or microorganisms, are considered to have a high potential therapeutic value and are of interest to be applied in the elucidation of biological recognition processes, due to their glucosidase inhibition properties. The great potency and specificity of these inhibitors are related to their ability to mimic transition-state pyranosidic or furanosidic units of natural glucosidase substrates. Currently, three drugs are therapeutically used as anti-glucosidases: acarbose (1) (Precose®), miglitol (2) (Glyset®) and N-butyl-1-deoxynojirimycin (3) (Zavesca®). Drugs 1 and 2 are used in the treatment of non-insulin-dependent diabetes, type II, since they reduce the postprandial hyperglycemia by interfering with the digestion of dietary carbohydrates, while drug 3 is employed for the control of Gaucher’s disease, related to disturbed lysosomal storage. This research proposal focuses on the synthesis and biological evaluation of pseudo-disaccharides with potential anti-glucosidase activity. Using different molecular modelling tools and drugs design strategies, new O-linked sugar iminoglycosides will be prepared, having the active unit of deoxynojirimycin as a scaffold. The in vitro tests of the potential inhibitors will involve glucosidase enzymes, antimicrobial, antifungal, antiviral activities, and toxicity.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ZAMONER, LUIS O. B.; ARAGAO-LEONETI, VALQUIRIA; CARVALHO, IVONE. Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities. PHARMACEUTICALS, v. 12, n. 3 SEP 2019. Web of Science Citations: 0.

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