Dipartimento di Chimica Organica “Ugo Schiff”

Prof. Francesca Cardona

Universita degli Studi di Firenze

Abstract

Engineering a 3,4,5-trihydroxypiperidine iminosugar in search of new GCase enhancers

The enzyme acid glucosidase ß-glucocerebrosidase (also known as GCase), is deputed to the hydrolysis of glucosylceramide in the lysosomes. Misfolding of GCase is triggered by genetic mutations and not only is the main cause of Gaucher disease (GD), the most frequent among the lysosomal storage diseases (LSDs), but has recently attracted renew attention for its interplay with α-synuclein. The latter is an intrinsically disordered protein whose aggregation contributes to Parkinson’s Disease (PD) pathogenesis, nowadays one of the most impactful neurodegenerative disorders. Thus, GCase emerges as a promising therapeutic target to address both pathologies. Pharmacological chaperones are small molecules able to bind misfolded enzymes, helping to rescue their physiological function by enhancing their hydrolytic activity.
Widely known as inhibitors of glycosidases and glycosyl transferases, iminosugars (ie glycomimetics where nitrogen replaces the endocyclic oxygen of carbohydrates) have recently gained attention as pharmacological chaperones for GCase.
I will drive you in our 10-years journey to access new task-specific iminosugars as pharmacological chaperones for GCase based on a 3,4,5- trihydroxypiperidine core derived from D-mannose.
Precision-engineered modifications and decoration of this compound with task-specific moieties can not only enhance affinity and selectivity towards the biological target [1], but also maximize the chaperoning vs inhibitory properties by means of stimuli responsive moieties [2][3]. The multivalent presentation of this glycomimetic was also investigated, greatly enhancing the biological response towards the target enzyme [4].
Moreover, since the addressed diseases (GD and PD) are often multisystemic and multifactorial, the classic “one-molecule, one-target” paradigm is unable to address their wide complexity. Therefore, introduction of additional functionalities on the glycomimetic core allowed to interact with additional targets other than GCase but involved in the pathologies of interest, such as α-synuclein [5] or reactive oxygen species [3][6].

Acknowledgements: The most recent researches described in this work were funded under the NRRP, M4C2 investment of MUR funded by #NEXTGENERATIONEU (NGEU) (Bando Prin 2022, Project code 2022N9E847—project: MULTIFUN. CUP: B53D23015580006 and project MNESYS-PE0000006- A Multiscale integrated approach to the study of the nervous system in health and disease (DR. 1553 11.10.2022)).

References

[1] F. Clemente et al, ACS Med. Chem. Lett. 2019, 10, 621
[2] F. Clemente et al, Chem. Eur. J. 2023, 29, e202203841
[3] M. G. Davighi et al, Eur. J. Med. Chem. 2025, 290, 117529
[4] C. Vanni et al, ChemBioChem 2022, 23, e202200077
[5] G. Tagliaferro et al, ACS Chem. Neurosci. 2025, 16, 1251
[6] D. Pratesi et al, Bioorg. Med. Chem. 2026, 132, 118453

About Prof Dr Alexander Titz

Professional Experience and Scholarships

Since 1° October 2015 – Associated Professor of Organic Chemistry at the University of Florence (Department of Chemistry).

Since 2002-Researcher (Assistant Professor) at the University of Florence (Department of Organic Chemistry).

2001-2002 Research fellowship, Department of Organic Chemistry, Florence. Title of the project: “Stereoselective Syntheses of Biologically Active Heterocycles”.
2001 (8 months) Work agreement contract between F. Cardona and CINMPIS

2000-2001 CNR (Consiglio Nazionale delle Ricerche) fellowship, Department of Organic Chemistry, Florence. Title of the project: “Stereoselective Synthesis of Biologically Active Hydroxylated Alkaloids and their Analogues”.

1999-2000 Postdoctoral Fellow. Group of Prof. Pierre Vogel, Lausanne, Switzerland. Title of the project: “Syntheses of D-mannose and D-galactose-derived C(1-3linked)-azadisaccharides by cross-aldolisation on naked sugars”

Education

1995-1999 (22/02/1999) Doctoral Degree in Chemical Sciences (equivalent to PhD), Department of Organic Chemistry, University of Florence. Title: “Synthesis and Computational Studies of Glycosidase Inhibitors”. Tutor: Prof. Alberto Brandi. The PhD research work focussed on the total syntheses of pyrrolidine and indolizidine alkaloids and their analogues using enantiomerically pure nitrones as key intermediates. A molecular dynamic study of two natural amyloglucosidase inhibitors, namely deoxynojirimycin and lentiginosine, within the enzyme cavity was also performed (at the University of Siena, under the supervision of Prof. Mangani).

1994-1995 Thesis Research Work, Department of Organic Chemistry, University of Florence. Title: “Cycloaddition reactions to enantiopure hydroxylated nitrones: synthesis of di- and trihydroxyindolizidines inhibitors of glycosidases”. Tutor: Dr. Andrea Goti.

1990-1995 Laurea in Chemistry (Organic Synthesis). Magna cum Laude: 110/110 et laude.

1985-1990 Maturità Scientifica at Liceo Scientifico “Morgagni”, Firenze, Italy. 60/60.

International experiences

Warsaw, Poland, August 1997, Institut of Organic Chemistry, Polish Academy of Sciences (PAN): “Cycloaddition of nitrones to sugar derivatives under high pressure” within the common project CNR-PAN 1997-1999.

Lausanne, Switzerland, 1997-1998 (Stage), 1999-2000 (Post-Doc), Institut of Organic Chemistry, University of Lausanne, Prof. Vogel group. Title of the project: Syntheses of D-mannose and D-galactose-derived C(1-3linked)-azadisaccharides by cross-aldolisation on naked sugars”

__________________

Invited Lecture – Engineering a 3,4,5-trihydroxypiperidine iminosugar in search of new GCase enhancers