A Rapid and Efficient Building Block Approach for Click Cyclization of Peptoids

Samarasimhareddy, Mamidi; Shamir, Mai; Shalev, Deborah E.; Hurevich, Mattan; Friedler, Assaf

doi:10.3389/fchem.2020.00405

Cited by 4 publications

(4 citation statements)

References 61 publications

(75 reference statements)

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“…While peptides suffer from proteolytic instability and have low bioavailability, [50][51][52] these challenges can be addressed using known modifications, [53] including the introduction of non-natural amino acid residues [54] and cyclization. [55,56] Targeting the PPI mediated by large interaction interfaces (hotspots) in enzymes, which has been receiving growing attention, significantly increases the amount of druggable proteins targets. [57,58] Since peptides represent the natural binding sequences of these hotspots and have much larger interaction interface compared with small molecules, they are excellent candidates for targeting PPI.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, modulating the sequences of peptides for the same purpose, is usually a quicker and easier process that bares minimal synthetic challenges. While peptides suffer from proteolytic instability and have low bioavailability, [50–52] these challenges can be addressed using known modifications, [53] including the introduction of non‐natural amino acid residues [54] and cyclization [55,56] . Targeting the PPI mediated by large interaction interfaces (hotspots) in enzymes, which has been receiving growing attention, significantly increases the amount of druggable proteins targets [57,58] .…”

Section: Discussionmentioning

confidence: 99%

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Peptide‐Based Inhibitors that Target the Docking Site of ERK2

Solomon

Shpilt

Sapir

et al. 2022

Israel Journal of Chemistry

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Abnormal kinase activity is highly associated with disease, especially cancer. Thus, kinases are important targets for developing anti‐cancer drugs. The common approach for kinase inhibition is using small molecules that compete with ATP for binding the ATP‐binding site of the kinase. However, since the ATP‐binding site is in many cases common to numerous kinases, it is difficult to achieve selectivity when targeting this site. Here we present an alternative approach of targeting the protein‐protein interactions of kinases as means for achieving selectivity in their inhibition. We demonstrate this approach by using peptides for inhibiting the docking D‐recruitment site (DRS) of the kinase ERK2. We designed a library of peptides, derived from DRS binding sequences of ERK2‐binding proteins. We synthesized the peptides and quantified their interactions with ERK2. Three peptides, derived from the proteins ELK1, SAP1 and SAP2, bound ERK2 in the low micromolar range. These peptides also inhibited the interaction of ERK2 with a surface‐bound ELK1 derived peptide. The peptides penetrated HT29 colon cancer cells and induced a moderate decrease in cell viability. Our approach can be further utilized for developing selective peptide‐based kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Peptide‐Based Inhibitors that Target the Docking Site of ERK2

Solomon

Shpilt

Sapir

et al. 2022

Israel Journal of Chemistry

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“…Cyclic peptide–peptoid hybrids synthesized from HIV-1 integrase (IN)-derived peptide IN 181–188 have an improved biological activity and high stability, compared to linear peptides. Click chemistry optimized by microwave-assisted automate solid phase synthesis (MW-SPPS), a rapid method lasting only a few hours, enabled a library of cyclic peptide–peptoid hybrids to be obtained [ 109 ].…”

Section: 123-triazoles In Other Mimeticsmentioning

confidence: 99%

1,2,3-Triazoles as Biomimetics in Peptide Science

2021

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Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

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“…Several reviews have reported the click reaction as essential in numerous fields—for instance, in polymer grafting [ 15 ], in the synthesis of 1,2,3-triazole scaffolds [ 16 ], and in chemical ligation [ 17 ]. Recently, reported works have declared applications in the achievement of peptidomimetics [ 18 ], in surface chemistry [ 19 ], and in bio-conjugations [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

New 1,2,3-Triazole-Containing Hybrids as Antitumor Candidates: Design, Click Reaction Synthesis, DFT Calculations, and Molecular Docking Study

et al. 2021

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In an effort to improve and achieve biologically active anticancer agents, a novel series of 1,2,3-triazole-containing hybrids were designed and efficiently synthesized via the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of substituted-arylazides with alkyne-functionalized pyrazole-[1,2,4]-triazole hybrids. The structure geometry of these new clicked 1,2,3-triazoles was explored by density functional theory (DFT) using the B3LYP/6-311++G(d,p) level; also, the potential activity of the compounds for light absorption was simulated by time-dependent DFT calculations (TD-DFT). The antitumor impacts of the newly synthesized compounds were in vitro estimated to be towards the human liver cancer cell line (HepG-2), the human colon cancer cell line (HCT-116), and human breast adenocarcinoma (MCF-7). Among the tested compounds, conjugate 7 was the most potent cytotoxic candidate towards HepG-2, HCT-116, and MCF-7, with IC50 = 12.22, 14.16, and 14.64 µM, respectively, in comparison to that exhibited by the standard drug doxorubicin (IC50 = 11.21, 12.46, and 13.45 µM). Finally, a molecular docking study was conducted within the epidermal growth factor receptor (EGFR) active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that analogies 7, 6, and 5 could be considered as decent lead candidate compounds for anticancer agents.

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A Rapid and Efficient Building Block Approach for Click Cyclization of Peptoids

Cited by 4 publications

References 61 publications

Peptide‐Based Inhibitors that Target the Docking Site of ERK2

Peptide‐Based Inhibitors that Target the Docking Site of ERK2

1,2,3-Triazoles as Biomimetics in Peptide Science

New 1,2,3-Triazole-Containing Hybrids as Antitumor Candidates: Design, Click Reaction Synthesis, DFT Calculations, and Molecular Docking Study

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