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5 results on '"Carotti, Andrea"'

4. α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) Inhibitors as Novel Modulators of de novoNicotinamide Adenine Dinucleotide (NAD+) Biosynthesis

Author

Pellicciari, Roberto, Liscio, Paride, Giacchè, Nicola, De Franco, Francesca, Carotti, Andrea, Robertson, Janet, Cialabrini, Lucia, Katsyuba, Elena, Raffaelli, Nadia, and Auwerx, Johan

Abstract

NAD+has a central function in linking cellular metabolism to major cell signaling and gene regulation pathways. Defects in NAD+homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Whilst the beneficial effects of NAD+boosting are well established in mitochondrial fitness, metabolism, and lifespan, to date, no therapeutic enhancers of de novo NAD+biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22) the first potent and selective inhibitor of human ACMSD (IC50= 0.013 µM) that increase NAD+levels in cellular systems. Results of physicochemical properties, ADME, and safety profiling, coupled with in vivo target engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD+biosynthesis and position 22 as a first in class molecule for evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD+supply and/or homeostasis.

Published
2024
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5. Discovery and Structure-Activity Relationships of Novel ss DAF-12 Receptor Modulators.

Author

Ceccarelli G, Goracci L, Carotti A, Paccoia F, Passeri D, Cipolloni M, Di Bona S, Cruciani G, Pellicciari R, and Gioiello A

Subjects
Animals, Humans, Steroids therapeutic use, Life Cycle Stages, Structure-Activity Relationship, Strongyloidiasis drug therapy, Strongyloidiasis parasitology, Strongyloides stercoralis metabolism
Abstract

The nuclear receptor ss DAF-12 has been recognized as the key molecular player regulating the life cycle of the nematode parasite Strongyloides stercoralis . ss DAF-12 ligands permit the receptor to function as an on/off switch modulating infection, making it vulnerable to therapeutic intervention. In this study, we report the design and synthesis of a set of novel dafachronic acid derivatives, which were used to outline the first structure-activity relationship targeting the ss DAF-12 receptor and to unveil hidden properties shared by the molecular shape of steroidal ligands that are relevant to the receptor binding and modulation. Moreover, biological results led to the discovery of sulfonamide 3 as a submicromolar ss DAF-12 agonist endowed with a high receptor selectivity, no toxicity, and improved properties, as well as to the identification of unprecedented ss DAF-12 antagonists that can be exploited in the search for novel chemical tools and alternative therapeutic approaches for treating parasitism such as Strongyloidiasis.

Published
2024
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