Cyclic Peptides as Protein Kinase Inhibitors: Structure–Activity Relationship and Molecular Modeling

Sanner, Michel F.; Zoghebi, Khalid; Hanna, Samara E; Mozaffari, Saghar; Rahighi, Simin; Tiwari, Rakesh; Parang, Keykavous

doi:10.1021/acs.jcim.1c00320

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…1,2 In contrast, macrocyclic drugs like cyclic peptides can bind to larger binding sites with flat profiles or protein–protein interfaces. 6–12 Cyclization has the added benefit that it prevent rapid metabolic clearance. 13 Therefore, cyclic peptides have the potential to vastly extend the scope of druggable proteins and lead to therapeutics for currently untreatable diseases.…”

Section: Introductionmentioning

confidence: 99%

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

et al. 2022

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“…We have previously reported the synthesis and evaluation of hybrid cyclic linear [R 5 K]W 7 A-Dox conjugate in different cancer cell lines [ 29 ]. The rationale for designing [(WR) 8 WKβA]-Dox conjugate was based on the fact that we found cyclic peptide [WR] 9 composed of alternate R and W was a more potent kinase inhibitor than [WR] 5 and [R 5 K]W 7 against c-Src, Abl, PKCa, Braf, Cdk2/cyclin A1, and that Lck [ 28 ]. [WR] 9 was a superior molecular transporter versus [WR] 5 [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

“…Among all synthesized peptides, [WR] 9 was found to be the most effective peptide as a molecular transporter of fluorescence-labeled phosphopeptide (F′-GpYEEI) by 20-fold, compared to 4-fold when [WR] 5 was used. Furthermore, [WR] 9 has shown potent protein kinase (a protein that has been shown to be associated with unregulated cell signal transduction in cancer cells) inhibitory activity when compared with other synthesized peptides [WR] 5–8 [ 28 ]. Herein, we report the preparation of an amphiphilic cyclic peptide containing alternative tryptophan (W) and arginine (R) residues and a lysine containing a free side chain amino group through the covalent conjugation with a 3-carbon chain linker attached to Dox 14-hydroxyl group to afford [(WR) 8 WKβA]-Dox conjugate.…”

Section: Introductionmentioning

confidence: 99%

[(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

Zoghebi

Aliabadi

Tiwari

et al. 2022

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Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]9 containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)8WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the corresponding physical mixture of the peptide and Dox to evaluate the effectiveness of synthesized conjugate compared to the parent drug alone. [(WR)8WKβA]-Dox conjugate showed higher antiproliferative activity at 10 µM and 5 µM than Dox alone at 5 μM. The conjugate inhibited the cell viability of ovarian adenocarcinoma (SK-OV-3) by 59% and the triple-negative breast cancer cells MDA-MB-231 and MCF-7 by 71% and 77%, respectively, at a concentration of 5 μM after 72 h of incubation. In contrast, Dox inhibited the proliferation of SK-OV-3, MDA-MB-231, and MCF-7 by 35%, 63%, and 57%, respectively. Furthermore, [(WR)8WKβA]-Dox conjugate (5 µM) inhibited the cell viability of Dox-resistant cells (MES-SA/MX2) by 92%, while the viability of cells incubated with free Dox was only 15% at 5 μM. Confocal microscopy images confirmed the ability of both Dox conjugate and the physical mixture of the peptide with the drug to deliver Dox through an endocytosis-independent pathway, as the uptake was not inhibited in the presence of endocytosis inhibitors. The stability of Dox conjugate was observed at different time intervals using analytical HPLC when the conjugate was incubated with 25% human serum. Half-life (t1/2) for [(WR)8WKβA]-Dox conjugate was (∼6 h), and more than 80% of the conjugate was degraded at 12 h. The release of free Dox was assessed intracellularly using the CCRF-CEM cell line. The experiment demonstrated that approximately 100% of free Dox was released from the conjugate intracellularly within 72 h. These data confirm the ability of the cyclic cell-penetrating peptide containing tryptophan and arginine residues as an efficient tool for delivery of Dox and for overcoming resistance to it.

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“… 10 − 12 In comparison to small molecules, macrocyclic compounds hold the potential to vastly extend the scope of druggable proteins. Due to their ability to target larger binding sites with flat profiles, 4 , 13 − 17 like protein–protein interaction (PPI) interfaces, 18 − 20 they can lead to new therapeutics for currently untreatable diseases. However, high binding affinity to a target is not enough for a molecule to be pharmaceutically relevant.…”

Section: Introductionmentioning

confidence: 99%

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes

et al. 2023

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Cyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also their passive membrane permeability. As the “journey” through membranes cannot be monitored experimentally, little is known about the underlying process, which hinders rational design. Here, we use molecular simulations to uncover how cyclic peptides permeate a membrane. We show that side chains can act as “molecular anchors”, establishing the first contact with the membrane and enabling insertion. Once inside, the peptides are positioned between headgroups and lipid tailsa unique polar/apolar interface. Only one of two distinct orientations at this interface allows for the formation of the permeable “closed” conformation. In the closed conformation, the peptide crosses to the lower leaflet via another “anchoring” and flipping mechanism. Our findings provide atomistic insights into the permeation process of flexible cyclic peptides and reveal design considerations for each step of the process.

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Cyclic Peptides as Protein Kinase Inhibitors: Structure–Activity Relationship and Molecular Modeling

Cited by 9 publications

References 36 publications

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

Polar/apolar interfaces modulate the conformational behavior of cyclic peptides with impact on their passive membrane permeability

[(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes

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