Design of cyclic and <scp>d</scp>‐amino acids containing peptidomimetics for inhibition of protein‐protein interactions of HER2‐HER3

Pallerla, Sandeep; Naik, Himgauri; Singh, Sitanshu S.; Gauthier, Ted J.; Sable, Rushikesh; Jois, Seetharama D.

doi:10.1002/psc.3066

Cited by 10 publications

(9 citation statements)

References 50 publications

(63 reference statements)

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“…The result of this lack of recognition is that while most l-peptides are vulnerable to enzymatic degradation in vivo [22], analogous d-peptides are highly resistant to degradation by proteases and have low immunogenicity [47,48]. The simple substitution of all l-amino acids in a peptide with d-amino acids, however, is generally an ineffective strategy as the resulting changes in peptide conformation and side chain orientation can prevent the correct binding geometry and thus destroy target binding [49][50][51][52]. A common solution to this issue is retro-inversion, which constitutes reversing the d-peptide's sequence ( Figure 5).…”

Section: D-amino Acidsmentioning

confidence: 99%

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

et al. 2020

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The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of d- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals.

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Section: D-amino Acidsmentioning

confidence: 99%

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

et al. 2020

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“…Interestingly, the replacement of l -amino acids by d -amino acids not only increased serum stability, but also improved the binding affinity of the peptide, potentiating its effect. Another example is provided by peptidomimetics targeting the HER2-mediated dimerization of the epidermal growth factor receptor, which show increased antiproliferative activity in cancer cell lines when stabilized using d -amino acids [160]. Analogous to this approach, so-called d -amino acid-containing supramolecular nanofibers have been suggested to play an important role in the development of cancer therapeutics in the near future, as extensively reviewed by Wang et al [161].…”

Section: D-amino Acids In Diseasementioning

confidence: 99%

d-amino Acids in Health and Disease: A Focus on Cancer

et al. 2019

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d-amino acids, the enantiomeric counterparts of l-amino acids, were long considered to be non-functional or not even present in living organisms. Nowadays, d-amino acids are acknowledged to play important roles in numerous physiological processes in the human body. The most commonly studied link between d-amino acids and human physiology concerns the contribution of d-serine and d-aspartate to neurotransmission. These d-amino acids and several others have also been implicated in regulating innate immunity and gut barrier function. Importantly, the presence of certain d-amino acids in the human body has been linked to several diseases including schizophrenia, amyotrophic lateral sclerosis, and age-related disorders such as cataract and atherosclerosis. Furthermore, increasing evidence supports a role for d-amino acids in the development, pathophysiology, and treatment of cancer. In this review, we aim to provide an overview of the various sources of d-amino acids, their metabolism, as well as their contribution to physiological processes and diseases in man, with a focus on cancer.

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“…Structure-activity relationships of 18 ( Fig. 1) and analogs and their effect on HER2-positive breast cancer were described in our previous reports [20,30,[38][39][40][41][42].…”

Section: Design Of the Peptidomimetic Compound 18mentioning

confidence: 75%

In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC

et al. 2020

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Studies related to lung cancer have shown a link between human epidermal growth factor receptor-2 (HER2) expression and poor prognosis in patients with non-small cell lung cancer (NSCLC). HER2 overexpression has been observed in 3-38% of NSCLC, while strong HER2 protein overexpression is found in 2.5% of NSCLC. However, HER2 dimerization is important in lung cancer, including EGFR mutated NSCLC. Since HER2 dimerization leads to cell proliferation, targeting the dimerization of HER2 will have a significant impact on cancer therapies. A peptidomimetic has been designed that can be used as a therapeutic agent for a subset of NSCLC patients overexpressing HER2 or possessing HER2 as well as EGFR mutation. A cyclic peptidomimetic (18) has been designed to inhibit protein-protein interactions of HER2 with its dimerization partners EGFR and HER3. Compound 18 exhibited antiproliferative activity in HER2-positive NSCLC cell lines at nanomolar concentrations. Western blot analysis showed that 18 inhibited phosphorylation of HER2 and Akt in vitro and in vivo. Stability studies of 18 at various temperature and pH (pH 1 and pH 7.6), and in the presence of liver microsomes indicated that 18 was stable against thermal and chemical degradation. Pharmacokinetic parameters were evaluated in nude mice by administrating single doses of 4 mg/kg and 6 mg/kg of 18 via IV. The anticancer activity of 18 was evaluated using an experimental metastasis lung cancer model in mice. Compound 18 suppressed the tumor growth in mice when compared to control. A proximity ligation assay further proved that 18 inhibits HER2:HER3 and EGFR: HER2 dimerization. Overall, these results suggest that 18 can be a potential treatment for HER2-dimerization related NSCLC.

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Design of cyclic and d‐amino acids containing peptidomimetics for inhibition of protein‐protein interactions of HER2‐HER3

Cited by 10 publications

References 50 publications

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

d-amino Acids in Health and Disease: A Focus on Cancer

In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC

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