Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Huo, Yuantao; Buckton, Laura K.; Bennett, Jack L.; Smith, Eloise C.; Byrne, Frances L.; Hoehn, Kyle L.; Rahimi, Marwa N.; McAlpine, Shelli R.

doi:10.1080/14756366.2019.1580276

Cited by 3 publications

(4 citation statements)

References 52 publications

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“…Further investigation confirmed that the identity of the binding region was a MEEVD motif in the C-terminus. LB76 restrains the protein-folding function of HSP90, thus blocking protein-protein interactions between HSP90 and co-chaperones (113,114). A de novo delivery system for LB76 produced by polymer nanoparticles and functioning by delivering LB76 into cells and releasing them in a pH-responsive manner, displayed improved inhibitory activity (115).…”

Section: Old and New Anti-neoplastic Treatments Targeting Hsp90mentioning

confidence: 99%

HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)

Luo

2022

Oncol Rep

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Heat shock protein 90 (HSP90) is a vital chaperone protein, regulating signaling pathways and correcting misfolded proteins in cancer cells by interacting with oncogenic client proteins and co-chaperones. The inhibition of HSP90 chaperone machinery has been demonstrated as a potential approach with which to inhibit tumor survival, proliferation, invasion and migration. Numerous HSP90 inhibitors have been reported and have exhibited value as cancer-targeted therapies by interrupting the ATPase activity of HSP90, thus suppressing the oncogenic pathways in cancer cells. These inhibitors have been classified into three categories: i) N-terminal domain (NTD) inhibitors; ii) C-terminal domain (CTD) inhibitors; and iii) isoform-selective inhibitors. However, none of these HSP90 inhibitors are used as clinical treatments. The major limiting factors can be summarized into drug resistance, dose-limiting toxicity and poor pharmacokinetic profiles. Novel HSP90-targeted compounds are constantly being discovered and tested for their antitumor efficacy in preclinical and clinical trials, highlighting the prospect of the use of HSP90 inhibitors as cancer-targeted therapies. Additionally, improved antitumor effects have been observed when HSP90 inhibitors are used in combination with chemotherapy, targeted agents, or immunotherapy. In the present review, the effects of HSP90 inhibitors on the management of the cancer process are discussed and previous and novel HSP90-based therapeutic strategies in cancer treatment are summarized. Furthermore, prospective HSP90-targeting candidates are proposed for their future evaluation as cancer treatments. Contents 1. Introduction 2. Structure and biological function of HSP90 3. HSP90 as a druggable target in cancer therapy 4. Old and new anti-neoplastic treatments targeting HSP90 5. Conclusions and future perspectives

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Section: Old and New Anti-neoplastic Treatments Targeting Hsp90mentioning

confidence: 99%

HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)

Luo

2022

Oncol Rep

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“…For example, in a study of cyclic RGD peptides by Kessler et al, , masking of the arginine side chain with a carbamate and the aspartic acid with an ester was shown to improve cell permeation. Similarly, masking of a lysine residue with methyl groups improved permeation of cyclic pentapeptides targeting HSP60 …”

Section: Can Bro5 Permeation Be Improved By Making Prodrugs?mentioning

confidence: 99%

“…Similarly, masking of a lysine residue with methyl groups improved permeation of cyclic pentapeptides targeting HSP60. 46 Compared to small molecules and peptides, bRo5 compounds have high MWs and larger numbers of HBAs and HBDs. In this case, the addition of masking groups to HBDs could conceivably assist permeation.…”

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confidence: 99%

Improving Membrane Permeation in the Beyond Rule-of-Five Space by Using Prodrugs to Mask Hydrogen Bond Donors

et al. 2020

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A wide range of drug targets can be effectively modulated by peptides and macrocycles. Unfortunately, the size and polarity of these compounds prevents them from crossing the cell membrane to reach target sites in the cell cytosol. As such, these compounds do not conform to standard measures of drug-likeness and exist in beyond the rule-of-five space. In this work, we investigate whether prodrug moieties that mask hydrogen bond donors can be applied in the beyond rule-of-five domain to improve the permeation of macrocyclic compounds. Using a cyclic peptide model, we show that masking hydrogen bond donors in the natural polar amino acid residues (His, Ser, Gln, Asn, Glu, Asp, Lys, and Arg) imparts membrane permeability to the otherwise impermeable parent molecules, even though the addition of the masking group increases the overall compound molecular weight and the number of hydrogen bond acceptors. We demonstrate this strategy in PAMPA and Caco2 membrane permeability assays and show that masking with groups that reduce the number of hydrogen-bond donors at the cost of additional mass and hydrogen bond acceptors, a donor–acceptor swap, is effective.

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“…Acetyl groups are also frequently used to mask alcohols, phenols, and amines in order to improve drug pharmacokinetics, [97] and the acetyl group on aspirin must be cleave by esterases in order to reveal the active drug [98] . Using commercially available liver microsomes the O‐ and N‐dealkylation processes of LB55 were evaluated [99] and after 180 minutes it was clear from the LCMS that there was no dealkylation [100] . Since O‐ and N‐dealkylation processes failed upon treatment with liver enzymes designed to unmask these groups, acetyl groups were investigated, where esterases are readily available in these enzymes.…”

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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121

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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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Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

Cited by 3 publications

References 52 publications

HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)

HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)

Improving Membrane Permeation in the Beyond Rule-of-Five Space by Using Prodrugs to Mask Hydrogen Bond Donors

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

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