A5081974161- Biochemical and Molecular Research
- Colorectal Cancer Treatments and Studies
- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Trypanosoma species research and implications
- Synthesis and Biological Evaluation
- Antibiotic Resistance in Bacteria
- Synthesis and biological activity
- Enzyme Structure and Function
- Cancer, Hypoxia, and Metabolism
- Research on Leishmaniasis Studies
- Pharmaceutical and Antibiotic Environmental Impacts
- Hippo pathway signaling and YAP/TAZ
- Biosensors and Analytical Detection
- Cancer Research and Treatments
- Photonic and Optical Devices
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Click Chemistry and Applications
- Influenza Virus Research Studies
- Antibiotics Pharmacokinetics and Efficacy
- Respiratory viral infections research
- Bacterial Identification and Susceptibility Testing
- Ocular Infections and Treatments
- Retinoids in leukemia and cellular processes
University of Modena and Reggio Emilia
2014-2023
University of Verona
2023
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three analogues (1-3) of published chromen-4-one derivatives were synthesized biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 Leishmania major-LmPTR1) parasites infantum). A crystal structure TbPTR1 in complex with compound first structures LmPTR1-flavanone complexes (compounds 3) solved....
Bacterial resistance has become a worldwide concern after the emergence of metallo-β-lactamases (MBLs). They represent one major mechanisms bacterial against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, most prevalent type, is extremely efficient in inactivating nearly all-available antibiotics including last resort carbapenems. No inhibitors for NDM-1 are currently available therapy, making spread producing strains serious menace. With this perspective, we...
Abstract β-Lactamases (BLs) able to hydrolyze β-lactam antibiotics and more importantly the last resort carbapenems, represent a major mechanism of resistance in Gram-negative bacteria showing multi-drug or extensively drug resistant phenotypes. The early detection BLs responsible infections is challenging: approaches aiming at identification new inhibitors (BLI) can thus serve as basis for development highly needed diagnostic tools. Starting from benzo-[b]-thiophene-2-boronic acid (BZB),...
Abstract Bacteria are known to evade β - lactam antibiotic action by producing β-lactamases (BLs), including carbapenemases, which able hydrolyze nearly all available β-lactams. The production of BLs represents one the best and most targeted mechanisms resistance in bacteria. We have performed parallel screening commercially compounds against a panel clinically relevant BLs: class A CTX-M-15 KPC-2, subclass B1 NDM-1 VIM-2 MBLs, C P. aeruginosa AmpC. results show that prefer scaffolds having...
Drug–target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates folic acid anticancer peptides able bind human thymidylate synthase (hTS) enter cancer cells through folate receptor α (FRα) highly expressed by several cells. Mechanistic analyses molecular modeling simulations shown that these the hTS monomer–monomer interface affinities over 20...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present systematic, multidisciplinary approach to development selective antiparasitic compounds. Computational fragment-based design novel pteridine derivatives along iterations crystallographic structure determination allowed for derivation structure–activity relationship multitarget inhibition. yielded showing apparent picomolar inhibition T. brucei reductase 1...
This paper reports the experimental assessment of an automated optical assay based on label free fiber optrodes for fast detection class C β-lactamases (AmpC BLs), actually considered as one most important sources resistance to β-lactams antibiotics expressed by resistant bacteria. Reflection-type long period gratings (RT-LPG) have been used highly sensitive optrodes, while a higher affine boronic acid-based ligand was here selected enhance overall performances compared those obtained in our...
Thymidylate synthase (TS) is a target for pemetrexed and the prodrug 5-fluorouracil (5-FU) that inhibit protein by binding at its active site. Prolonged administration of these drugs causes TS overexpression, leading to drug resistance. The peptide lead, LR (LSCQLYQR), allosterically stabilizes inactive form inhibits ovarian cancer (OC) cell growth with stable decreased dihydrofolate reductase (DHFR) expression. To improve inhibition anticancer effect, we have developed 35 peptides modifying...
According to the World Health Organization, more than 1 billion people are at risk of or affected by neglected tropical diseases. Examples such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all prevalent in Africa, South America, India. Our aim within New Medicines for Trypanosomatidic Infections project was use (1) synthetic natural product libraries, (2) screening, (3) a preclinical absorption, distribution, metabolism,...
Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with nonsubstrate analog inhibitor. Given active site similarities between Mycobacterium (Mtb-ThyX) and Tm-ThyX, our paves way structure-based design novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as...
Broad-spectrum anti-infective chemotherapy agents with activity against Trypanosomes, Leishmania, and Mycobacterium tuberculosis species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled identification synthesis 44 broad-spectrum antiparasitic minimal toxicity Trypanosoma brucei, Leishmania Infantum, cruzi. In vitro studies confirmed...
Abstract Demonstrating a candidate drug’s interaction with its target protein in live cells is of pivotal relevance to the successful outcome drug discovery process. Although thymidylate synthase (hTS) an important anticancer protein, efficacy few anti-hTS drugs currently used clinical practice limited by development resistance. Hence, there intense search for new, unconventional drugs; are approximately 1600 ongoing trials involving hTS-targeting drugs, both alone and combination protocols....
Allosteric peptide inhibitors of thymidylate synthase (hTS) bind to the dimer interface and stabilize inactive form protein. Four residues were mutated alanine, interaction studies employed decode key role these in molecular recognition. This led identification three crucial F59, L198, Y202 that impart activity suggest binding area for further inhibitor design.
Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development drug resistance. We thus pursued an alternative strategy led us to the discovery TS-dimer destabilizers. These compounds bind at monomer-monomer interface shift dimerization equilibrium both recombinant intracellular toward inactive monomers. A structural,...
Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of novel core structure inspiring new treatments parasitic diseases targeting trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate (DHFR) enzymes. In total, 592 compounds tested through medium-throughput assays. A subset 14 successfully inhibited enzyme activity in low micromolar...
The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in Hippo pathway involved cancer progression through modulation of activity TEAD enhanced associate domain) transcription factors. To exploit advantages drug repurposing search new drugs, we developed a similar approach for identification hits interfering target gene expression. In our study, 27-member in-house library was assembled,...
LR and [d-Gln4]LR peptides bind the monomer–monomer interface of human thymidylate synthase inhibit cancer cell growth. Here, proline-mutated were synthesized. Molecular dynamics calculations circular dichroism spectra have provided a consistent picture conformational propensities [Pron]-peptides. [Pro3]LR [Pro4]LR show improved growth inhibition similar intracellular protein modulation compared with LR. These represent step forward to identification more rigid metabolically stable peptides.
We report on the development of a multilayer coated reflection-type long period fiber grating (LPG) biosensor, useful for detection antibiotic resistance bacteria. A standard LPG is first transformed in more practical probe working reflection mode, then it by primary layer aPS and secondary PMMA order to increase its surrounding refractive index sensitivity at same time provide necessary conditions correct bio-functionalization. Standard linkage chemistry has been applied anchor bioreceptors...