Synthesis and Structure–Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90

Rahimi, Marwa N.; Buckton, Laura K.; Zaiter, Samantha S.; Kho, Jessica; Chan, Vickie; Guo, Aldwin; Konesan, Jenane; Kwon, SuHyeon; Lam, Lok K. O.; Lawler, Michael F.; Leong, Michael; Moldovan, Gabriel D.; Neale, David A.; Thornton, Gillian; McAlpine, Shelli R.

doi:10.1021/acsmedchemlett.7b00310

Cited by 24 publications

(12 citation statements)

References 18 publications

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“…The data showing that acetyl masking groups can only be removed from serine and tyrosine residues lead to the new design of prodrugs. Starting from two of our most effective compounds, LB51 and LB63, we designed new prodrugs using acetylated serine and tyrosine amino acids (Figure 5(a)) 32 .…”

Section: Resultsmentioning

confidence: 99%

“…We had previously reported molecules that targeted heat shock protein 90 (Hsp90), with the lead structures being LB51 and LB63 32 ,33 . However, these active inhibitors had poor cell permeability, and three approaches were used to make these molecules more effective at entering cells: masking groups 10 , d -amino acids 10 , and N -methylation 9 .…”

Section: Introductionmentioning

confidence: 99%

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Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Huo

Buckton

Bennett

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O -alkyl, (b) N -alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, P app, from 3.3 to 5.6, however alkyls could not be removed by liver microsomes or in-vivo and their presence decreased target binding affinity (IC 50 of ≥10 µM). Thus, unlike small molecules, peptide masking groups cannot be predictably removed; their removal is related to the 3-D conformation. O-acetyl groups were cleaved but are labile, increasing challenges during synthesis. Utilising acetyl groups coupled with mono-methylated amines may decrease the polarity of a peptide, while maintaining binding affinity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Huo

Buckton

Bennett

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Multiple sequence analysis of the ToHSP90β amino acid revealed that it has five conserved signal regions of the HSP90 family with other fish in Figure 2 (Gupta, 1995). The C-terminus of HSP90β has a conserved MEEVD structure that is a feature shared in all the cytosolic Heat shock protein 90 family (Scheufler et al, 2000;Qin et al, 2016;Zhou et al, 2017;Rahimi et al, 2018). Scheufler et al (2000) suggested that MEEVD can be recognized by the TPR domain of HOP (HSP70 and HSP90 organizing protein) and form a molecular chaperone complex with heat shock protein 70.…”

Section: Discussionmentioning

confidence: 99%

Characterization and expression analysis of heat shock protein 90β from golden pompano (Trachinotus ovatus, Linnaeus 1758) in responses to stock density stress and Cryptocaryon irritans infection

Guo

Yang

Liu

et al. 2021

Israeli Journal of Aquaculture - Bamidgeh

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Heat shock protein 90 family, a class highly conserved protein and important molecular chaperone and its plays a role in enhancing animal adaptability to environmental stress and improving immunity. In this study, a full-length HSP90β cDNA (ToHSP90β) sequence was identified from Trachinotus ovatus. The cDNA of ToHSP90β was 2648 base-pairs (bp) long and contained a 5′-terminal untranslated region of 130 bp, a 3′-terminal untranslated region of 334 bp, and the open reading frame length 2184 bp, which can encode 728 amino acids. The ToHSP90β has a heat shock protein 90 family signature. The ToHSP90β amino acid sequence has high homology with other fish HSP90β amino acids (92.5-99.17%) and contains five conserved signal regions and a structural feature of the cytoplasmic HSP90 family. Phylogenetic tree analysis indicated that ToHSP90β was most closely related to Seriola dumerili HSP90β. Tissues expression analysis showed that the ToHSP90β was expressed in all nine tissues of T. ovatus, and its expression was the highest in the intestine. The stocking density significantly affected the expression of ToHSP90β in the kidney and brain tissues, and its expression levels increased significantly with increasing stocking densities, indicating that it plays an important regulatory role in the process of T. ovatus' chronic stress response. After Cryptocaryon irritans infection, the mRNA expression of ToHSP90β was significantly increased in liver and kidney tissues, indicating that ToHSP90β would be involved in the immune regulatory response. This study was the first to analyze the expression pattern of HSP90β mRNA in T. ovatus tissues and their expression responses to stocking density stress and C. irritans infection. To provide a theoretical basis for further study of the function of fish HSP90 and its physiological mechanism in environmental stress and parasite infection.

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“…In addition to evaluating the impact of N‐methylation on LB51 (Figure 10), the McAlpine laboratory also investigated the effect of incorporating d ‐amino acids to generate diastereomers of this lead molecule (Figure 12). [30, 79] Inverting the stereochemistry of asparagine from l to d produced LB51 ‐ d ‐Asn, which had a Caco‐2 cell permeability of 3.9×10 −6 cm s −1 , which was slightly higher than the lead compound's permeability of 3.3×10 −6 cm s −1 . While the cell permeability was similar, incorporating a single d ‐amino acid had a negative impact on the biological activity, where only 25 % inhibition was achieved.…”

Section: Chemical Strategies For Optimizing the Cell Permeability Of mentioning

confidence: 99%

Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development

Buckton

Rahimi

McAlpine

2020

Chemistry A European J

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Developing macrocyclic peptides that can reach intracellular targets is a significant challenge. This review discusses the most recent strategies used to develop cell permeable cyclic peptides that maintain binding to their biological target inside the cell. Macrocyclic peptides are unique from small molecules because traditional calculated physical properties are unsuccessful for predicting cell membrane permeability. Peptide synthesis and experimental membrane permeability is the only strategy that effectively differentiates between cell permeable and cell impermeable molecules. Discussed are chemical strategies, including backbone N‐methylation and stereochemical changes, which have produced molecular scaffolds with improved cell permeability. However, these improvements often come at the expense of biological activity as chemical modifications alter the peptide conformation, frequently impacting the compound's ability to bind to the target. Highlighted is the most promising approach, which involves side‐chain alterations that improve cell permeability without impact binding events.

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Synthesis and Structure–Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90

Cited by 24 publications

References 18 publications

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Characterization and expression analysis of heat shock protein 90β from golden pompano (Trachinotus ovatus, Linnaeus 1758) in responses to stock density stress and Cryptocaryon irritans infection

Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development

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