Use of parallel-synthesis combinatorial libraries for rapid identification of potent FKBP12 inhibitors

Choi, Chi Yan; Li, Jia He; Vaal, Mark J.; Thomas, Christine K.; Limburg, David C.; Wu, Yong; Chen, Yi; Soni, Raj; Scott, Chad; Ross, Douglas T.; Guo, Hong; Howorth, P. J. N.; Valentine, Heather; Shi, Liang; Spicer, Dawn; Fuller, Mike; Steiner, Joseph P.; Hamilton, Gregory S.

doi:10.1016/s0960-894x(02)00147-6

Cited by 20 publications

(18 citation statements)

References 9 publications

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“…The time normally required may vary from 0.5 hour to 24 hours [91]. Several novel methodologies for large-scale screening for inhibitors of FKBPs have been recently published [122][123][124].…”

Section: ) Establishment Of the Binding Constants For Ppiase/inhibimentioning

confidence: 99%

Peptidylprolyl Cis / Trans Isomerases (Immunophilins): Biological Diversity - Targets - Functions

Gałat

2003

CTMC

344

302

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Information recovered from genome sequencing projects, multiple sequence alignments, structural analyses of PPIase and published records were used in deciphering the biological diversity, functions and targets of four groups of proteins encoded by dissimilar sets of sequences whose spatial representations exhibit peptidylprolyl cis/trans isomerase activity (PPIase). In the human genome there are encoded fifteen proteins whose segments have significant homology with the sequence of 12 kDa protein which is the target of the potent immunosuppressive macrolides FK506 or rapamycin. The 12 kDa archetype of the FK506-binding protein (FKBP), known as FKBP-12a, is an abundant intracellular protein whereas other FKBPs possessing from one to four FK506-like binding domains (FKBDs) have nominal masses varying from 13 to 135 kDa. The human genome contains at least sixteen genes encoding proteins comprising one cyclosporin-A (CsA) binding domain (CLD) called cyclophilins whose nominal masses vary from 17 to 324 kDa and multiple coding segments for small cyclophilins (17-19 kDa) whose transcription levels and functions remain unknown. The third group of PPIases encoded in the genome comprises two proteins (hPin1 and hParv14) where hPin1 is an important PPIase for cell cycle. The A. thaliana, C. elegans, D. melanogaster and S. cerevisiae genomes encode a less diverse spectrum of PPIases whereas the prokaryotic genomes contain from none to three cyclophilins, from none to four genes encoding FKBPs, one distant homologue of the Pin1 protein named parvulin and the fourth group of PPIases known as trigger factors. PPIases are discretely distributed to different cellular compartments and interact with a number of targets that control a range of cellular processes. Analyses of the sequence alignments of the two groups of PPIases, namely cyclophilins and FKBPs from diverse phyla, show that in each group their sequences diverge but the amino acid residues which form the PPIase activity site and macrolide binding cavity remain well conserved in the majority of them which suggests that the spatial structures and functions of each group of PPIases remain conserved.

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Section: ) Establishment Of the Binding Constants For Ppiase/inhibimentioning

confidence: 99%

Peptidylprolyl Cis / Trans Isomerases (Immunophilins): Biological Diversity - Targets - Functions

Gałat

2003

CTMC

344

302

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“…1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.37−7.31 (m, 5H), 6.99 (bs, 1H), 6.72 (bs, 1H), 5.16 (d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 4.15 (dd, J = 18.1, 6.1 Hz, 1H), 3.97−3.95 (m, 1H), 3.91 (dd, J = 18.1, 5.0 Hz, 1H), 3.09 (dd, J = 14.8, 3.2 Hz, 1H), 2.68−2.55 (m, 2H), 2.45 (dd, J = 14.4, 9.4 Hz, 1H). 13 Benzyl (o-Tolylcarbamoyl)-L-prolinate (18). Compound 17 (82 mg, 0.26 mmol, 1 equiv) was treated with TEA (73 μL, 0.52 mmol, 2 equiv) and o-tolyl isocyanate (36 μL, 0.29 mmol, 1.1 equiv) following GP1.…”

mentioning

confidence: 99%

Could Dissecting the Molecular Framework of β-Lactam Integrin Ligands Enhance Selectivity?

et al. 2019

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By dissecting the structure of β-lactam-based ligands, a new series of compounds was designed, synthesized, and evaluated toward integrins αvβ3, α5β1, and α4β1. New selective ligands with antagonist or agonist activities of cell adhesion in the nanomolar range were obtained. The best agonist molecules induced significant adhesion of SK-MEL-24 cells and Saos-2 cells as a valuable model for osteoblast adhesion. These data could lead to the development of new agents to improve cellular osseointegration and bone regeneration. Molecular modeling studies on prototypic compounds and αvβ3 or α5β1 integrin supported the notion that ligand carboxylate fixing to the metal ion-dependent adhesion site in the β-subunit can be sufficient for binding the receptors, while the aryl side chains play a role in determining the selectivity as well as agonism versus antagonism.

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“…Importantly, the switch between its folded and unfolded conformation is mediated by phosphorylation events that occur on multiple residues and, according to the specific phosphorylation site, can either enhance or reduce the affinity of CLIP170 for MTs. [50][51][52] Among the CLIP family members, CLIP115 that lacks the C-terminal zinc knuckles also exists, which precludes intramolecular folding. 53 As mentioned, CLIP170 is expressed in the developing nervous system 33 ; it forms comet-like structures in the cell body and in the neurites of expressing neurones.…”

Section: Clip170mentioning

confidence: 99%

“…In the extended conformation, CLIP170 operates as a rescue factor that converts shrinking MTs to growing ones. Importantly, the switch between its folded and unfolded conformation is mediated by phosphorylation events that occur on multiple residues and, according to the specific phosphorylation site, can either enhance or reduce the affinity of CLIP170 for MTs 50–52 . Among the CLIP family members, CLIP115 that lacks the C‐terminal zinc knuckles also exists, which precludes intramolecular folding 53 …”

Section: Molecular Targets Of Pme: Focus On the Mt Systemmentioning

confidence: 99%

Therapeutic potential of pregnenolone and pregnenolone methyl ether on depressive and CDKL5 deficiency disorders: Focus on microtubule targeting

Barbiero

Bianchi

Kilstrup‐Nielsen

2021

J Neuroendocrinology

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Pregnenolone methyl‐ether (PME) is a synthetic derivative of the endogenous neuroactive steroid pregnenolone (PREG), which is an important modulator of several brain functions. In addition to being the precursor of steroids, PREG acts directly on various targets including microtubules (MTs), the functioning of which is fundamental for the development and homeostasis of nervous system. The coordination of MT dynamics is supported by a plethora of MT‐associated proteins (MAPs) and by a specific MT code that is defined by the post‐translational modifications of tubulin. Defects associated with MAPs or tubulin post‐translational modifications are linked to different neurological pathologies including mood and neurodevelopmental disorders. In this review, we describe the beneficial effect of PME in major depressive disorders (MDDs) and in CDKL5 deficiency disorder (CDD), two pathologies that are joint by defective MT dynamics. Growing evidence indeed suggests that PME, as well as PREG, is able to positively affect the MT‐binding of MAP2 and the plus‐end tracking protein CLIP170 that are both found to be deregulated in the above mentioned pathologies. Furthermore, PME influences the state of MT acetylation, the deregulation of which is often associated with neurological abnormalities including MDDs. By contrast to PREG, PME is not metabolised into other downstream molecules with specific biological properties, an aspect that makes this compound more suitable for therapeutic strategies. Thus, through the analysis of MDDs and CDD, this work focuses attention on the possible use of PME for neuronal pathologies associated with MT defects.

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Use of parallel-synthesis combinatorial libraries for rapid identification of potent FKBP12 inhibitors

Cited by 20 publications

References 9 publications

Peptidylprolyl Cis / Trans Isomerases (Immunophilins): Biological Diversity - Targets - Functions

Peptidylprolyl Cis / Trans Isomerases (Immunophilins): Biological Diversity - Targets - Functions

Could Dissecting the Molecular Framework of β-Lactam Integrin Ligands Enhance Selectivity?

Therapeutic potential of pregnenolone and pregnenolone methyl ether on depressive and CDKL5 deficiency disorders: Focus on microtubule targeting

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