Probing Transition State Analogy in Glycoside Hydrolase Catalysis

Colombo, Cinzia; Bennet, Andrew J.

doi:10.1016/bs.apoc.2017.09.001

Cited by 13 publications

(22 citation statements)

References 81 publications

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“…In recent years, due to an increased understanding of transition state analogy in the context of GH enzymes, carbasugars have seen an application as mechanism‐based covalent inhibitors of GHs. A mechanism‐based covalent inhibitor is a compound that, bearing a structural similarity to an enzymatic substrate and also a reactive functionality, results in direct covalent binding to the enzyme and thus to its inactivation.…”

Section: Endocyclic Oxygen Replacementmentioning

confidence: 99%

Design and synthesis of glycomimetics: Recent advances

Tamburrini

Colombo

Bernardi

2019

Medicinal Research Reviews

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In the past few decades, our understanding of glycan information‐encoding power has notably increased, thus leading to a significant growth also in the design and synthesis of glycomimetic probes. Combining data from multiple analytical sources, such as crystallography, nuclear magnetic resonance spectroscopy, and other biophysical methods (eg, surface plasmon resonance and carbohydrate microarrays) has allowed to shed light on the key interaction events between carbohydrates and their protein‐targets. However, the low metabolic stability of carbohydrates and their high hydrophilicity, which translates in low bioavailability, undermine their development as drugs. In this framework, the design of chemically modified analogues (called carbohydrate mimics or glycomimetics) appears as a valid alternative for the development of therapeutic agents. Glycomimetics, as structural and functional mimics of carbohydrates, can replace the native ligands in the interaction with target proteins, but are designed to show enhanced enzymatic stability and bioavailability and, possibly, an improved affinity and selectivity toward the target. In the present account, we specifically focus on the most recent advances in the design and synthesis of glycomimetics. In particular, we highlight the efforts of the scientific community in the development of straightforward synthetic procedures for the preparation of sugar mimics and in their preliminary biological evaluation.

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Section: Endocyclic Oxygen Replacementmentioning

confidence: 99%

Design and synthesis of glycomimetics: Recent advances

Tamburrini

Colombo

Bernardi

2019

Medicinal Research Reviews

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“…For the enzyme-catalyzed reaction, k inact /K i is determined by the differences in free energy between the ground state (free substrate/inhibitor and enzyme in solution) and the rst irreversible step (cleavage of the glycosidic bond). 24,38,45,46 Therefore, we decided to use 19 F NMR spectroscopy to measure isotopologue ratios (R, the ratio of heavy-to-light isotopologues for the remaining starting material) as the reaction progressed (F, the fraction of reaction for the light isotopologue) to evaluate the secondary deuterium and 13 C-KIEs. 47,48 We note that because our syntheses involved enantioselective catalysis our covalent inhibitors are not enantiopure, as also would be the case with chiral pool starting materials, such as galactose.…”

Section: Measurement Of Kinetic Isotope Effects On Gh Covalent Labelingmentioning

confidence: 99%

“…1A). 5,[24][25][26] However, despite the tight binding that many carbasugars exhibit towards GHs, it remains controversial as to whether they are indeed TSA inhibitors. 24,[27][28][29] A more theoretically based approach to the design of TSAs has been used and incorporates the measurement of kinetic isotope effects (KIEs) with computational methods to determine the geometric and electronic structure of enzymatic transition states for the reactions involving natural substrates, [30][31][32] and to use this structural information to design of TSA inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…5,[24][25][26] However, despite the tight binding that many carbasugars exhibit towards GHs, it remains controversial as to whether they are indeed TSA inhibitors. 24,[27][28][29] A more theoretically based approach to the design of TSAs has been used and incorporates the measurement of kinetic isotope effects (KIEs) with computational methods to determine the geometric and electronic structure of enzymatic transition states for the reactions involving natural substrates, [30][31][32] and to use this structural information to design of TSA inhibitors. [33][34][35] In contrast to previous work on non-covalent inhibition of GHs, 36,37 we presented studies of small molecule alkenyl, e.g., 4, 38,39 and cyclopropyl 39,40 carbasugar probes that both covalently label GHs and we provided structural insights into the conformations of the enzyme bound and covalent intermediates that are present during GH inactivation (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design

et al. 2020

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“…For retaining sialidases, the glycosylated enzyme intermediate generated in the catalytic pocket is subjected to both glycosylation and deglycosylation via transition states (TS) that have an oxacarbenium ion character and feature a distorted six-membered ring ( Fig 2 ). [ 6 – 9 ] Oseltamivir ( 1 , Fig 1 ) uses a cyclohexene ring in place of the sugar pyran to mimic this distortion. The ring is substituted at both C4 and C6 with an amino group, replacing NeuAc hydroxyl groups, and at C-5 with a 3- pentyl ether chain in place of NeuAc glycerol side chain.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase

et al. 2018

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The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.

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Probing Transition State Analogy in Glycoside Hydrolase Catalysis

Cited by 13 publications

References 81 publications

Design and synthesis of glycomimetics: Recent advances

Design and synthesis of glycomimetics: Recent advances

Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design

Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase

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