AGlab –Asymmetric Synthesis of Biomimetics for Therapeutic Applications
Room 0Mb017; phone +39-081674119; email annalisa.guaragna@unina.it
OTHER GROUP MEMBERS:
Dr Anna Esposito (Postdoc)
RESEARCH LINES
1) L-Iminosugars: Emerging Glycomimetics
Iminosugars represent the most promising class of therapeutically useful glycomimetics. Because of their ability to mimic structure and properties of natural monosaccharides, iminosugars are able to interfere with disease-related carbohydrate-processing enzymes. Despite their great therapeutic potential, iminosugars suffer of poor selectivity, thereby leading to the onset of undesired side effects after prolonged administration. A valid alternative is offered by L-iminosugars, the non-superimposable mirror images of natural iminosugars which can act as either inhibitors or chaperones of various glycosidases, although working in a more markedly selective manner. The study on L-iminosugars has been widened to N-alkyl-L-iminosugars. Some of them are able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, or to exhibit an anti-inflammatory effect in Cystic Fibrosis (CF) bronchial cells, by targeting β-glucosidase 2 (GBA2). The same molecules showed an interesting pharmacological potential in Sanfilippo syndrome, with their ability to significantly reduce substrate storage and lysosomal dysfunctions in Sanfilippo fibroblasts and in a neuronal cellular model of Sanfilippo B subtype.
Main collaboration:
Prof. Giancarlo Parenti (University of Naples Federico II, Naples, Italy and Telethon Institute of Genetics and Medicine, Pozzuoli, Italy)
Prof. Luigi Michele Pavone (University of Naples Federico II, Naples, Italy)
Prof. Marco Moracci (Institute of Biosciences and Bioresources, CNR, Naples, Italy and University of Naples Federico II, Naples, Italy)
Prof. Frances Platt and Prof. Nicole Zitzmann (University of Oxford, Oxford, UK)
Dr Maria Cristina Dechecchi and Prof. Giulio Cabrini (University of Verona, Verona, Italy)
Dr Alessandra Bragonzi (IRCCS San Raffaele Scientific Institute, Milan, Italy)
2) Iminosugars as antibacterial agents
Over the last years, we investigated the antibacterial properties of some alkyl/acyl-l-DNJ derivatives. Starting from the enantiomerically pure l-DNJ, prepared by two novel procedures (a de novo or a carbohydrate-based route) tuned up in our labs, a small library of compounds equipped with different lipophilic N/O-alkyl and acyl moieties was synthesized. Biological assays revealed the ability of some derivatives to interfere with the growth and biofilm formation of various Gram-positive and negative bacteria or to act as anti-virulence agents. The antibacterial effect was also observed in vivo against multidrug-resistant pathogens4pointing out the value of this class of compounds as a non-traditional approach to contrast bacterial infections.
Main collaborations:
Prof. E. De Gregorio (University of Naples Federico II, Naples, Italy)
Prof. G. Cabrini and Prof. I. Lampronti (University of Ferrara, Ferrara, Italy)
Dr Maria Cristina Dechecchi (University Hospital of Verona, Verona, Italy)
Dr Alessandra Bragonzi (IRCCS San Raffaele Scientific Institute, Milan, Italy)
Luis J. V. Galietta (Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy)
3) Mirror-Image Molecular Systems (MIMS): Revisiting the Role of Chirality at Chemistry-Biology Interface
Bioactive chiral molecules often hold specific conformational and high-order structures associated with their stereochemical features; their structures are deeply connected with their properties and functions, including the ability for chiral recognition. Nevertheless, the relationships between stereochemistry of a bioactive molecule and its effective biological function are not always predictable. Even though it is often assumed that biomolecular recognition processes are stereospecific, many exceptions involving "mirror-image" bioactive compounds suggest that enantiospecificity could not be a universal trait related to biological function. Our investigations on MIMS exploit a synthetic method enabling preparation of enantiopure organic molecules by a three-carbon homologation of chiral electrophiles. This has led to the synthesis of a great number of compounds with potential antiviral (nucleoside analogues, iminosugars) and antisense (Homo-DNA, HNA, Imino-HNA) properties. Study of the conformational implications associated to such systems have led to intriguing results regarding diverse biomolecular recognition processes.
Main collaborations:
Prof. Arthur van Aerschot and Prof. Piet Herdewjin (Rega Institute for Medical Research Leuven, Belgium)
4) Sugar Modified Nucleosides: Biomimetics with antiviral potential
In the absence of effective vaccines able to control viral infections, clinical use of chemically modified nucleosides currently represents the core of any chemotherapeutic treatment aiming at a substantial and prolonged suppression of viral replication. Because of the structural relationship with their natural counterparts, synthetic nucleosides can deeply interfere with various viral life cycles, mainly at a transcriptional level, by blocking the information flow enclosed in the viral genomes. Among sugar-modified nucleosides, those having an unnatural five- or six-membered heterocyclic moiety (with both D- or L-configuration) as deoxyribose bioisostere have received considerable attention over the last two decades, owing to their remarkable antiviral properties. Our recent interest has been devoted to a more convenient and stereoselective method for the preparation of the well-known anti-HIV drug Lamivudine, and to the synthesis of six-membered carbocyclic nucleosides as well as of iminosugars-based nucleoside to be evaluated as new broad spectrum antiviral drugs.
Main collaborations:
Prof. Johan Neyts and Dr Graciela Andrei (Rega Institute for Medical Research, Leuven, Belgium).
5) Smart Drug Delivery Systems
A long-standing problem in cancer chemotherapy is the lack of tumor-specific treatments. Traditional therapy relies on the action of cytotoxic agents; unfortunately, they have very little or no specificity, leading to systemic toxicity and causing severe side effects. Therefore, the construction of smart drug delivery systems, which enable selective release of cytotoxic drug at the disease's site, is urgently needed. Our project is focused on the synthetic development of new molecular systems (carrier-linked prodrugs) able to be selectively internalized into tumor cells on the basis of the so-called "Trojan horse" strategy. Such approach relies on the use of a tumor recognition moiety (the folic acid), able to identify cancer cells as the target site, to which a cytotoxic agent (chlorambucil) is covalently bound by a suitable linker (oligoether or oligo-b-peptide chains). Thus, internalization of such molecular system allows entry of the prodrug into the cancer cell, in which the drug is then released by some intracellular events such as the intense enzymatic activity in cancer cells or by the strongly acidic medium of the lysosomes of tumor cells
ACTIVCE PROJECTS:
"Pharmacological chaperone therapy with N-substituted l-iminosugars for the treatment of Sanfilippo B disease" funded by Cure Sanfilippo Foundation (USA).
"Evaluation of anti-inflammatory treatments for CF lung disease in murine models of lung infection in vivo" funded by the Fondazione per la Fibrosi Cistica (FFC#23/2018, FFC#20/2019).
"Combining antimicrobial agents and virulence blockers against Pseudomonas aeruginosa-Staphylococcus aureus co-infections in Cystic Fibrosis" funded by FONDAZIONE PER LA RICERCA SULLA FIBROSI CISTICA (FFC#8/2024).
"Can old and new sweet glycomimetics act as antibacterial and antibiofilm agents in the treatment of CF lung disease infections?" funded by FONDAZIONE PER LA RICERCA SULLA FIBROSI CISTICA (FFC#13/2020).
Liposomal formulation of a novel dual acting agent with anti-inflammatory and anti-infective properties for Cystic Fibrosis lung disease treatment". Funded by EUROPEAN CYSTIC FIBROSIS SOCIETY (ECFS) and CYSTIC FIBROSIS (CF) EUROPE.