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Cell Oct 2022The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of...
The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of the Gα subunit, Gαs. GTPases remain largely undruggable given the difficulty of displacing high-affinity guanine nucleotides and the lack of other drug binding sites. We explored a chemical library of 10 cyclic peptides to expand the chemical search for inhibitors of this enzyme class. We identified two macrocyclic peptides, GN13 and GD20, that antagonize the active and inactive states of Gαs, respectively. Both macrocyclic peptides fine-tune Gαs activity with high nucleotide-binding-state selectivity and G protein class-specificity. Co-crystal structures reveal that GN13 and GD20 distinguish the conformational differences within the switch II/α3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Gαs/Gβγ signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Gαs provides a path for further development of state-dependent GTPase inhibitors.
Topics: GTP Phosphohydrolases; Guanine Nucleotides; Nucleotides; Peptides; Peptides, Cyclic; Receptors, G-Protein-Coupled
PubMed: 36170854
DOI: 10.1016/j.cell.2022.09.019 -
Current Medicinal Chemistry 2016For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen... (Review)
Review
For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.
Topics: Animals; Humans; Opioid Peptides; Pain; Peptides, Cyclic; Receptors, Opioid
PubMed: 27117332
DOI: 10.2174/0929867323666160427123005 -
Molecules (Basel, Switzerland) Jul 2022Cyclic peptides have been widely reported to have therapeutic abilities in the treatment of cancer. This has been proven through in vitro and in vivo studies against... (Review)
Review
Cyclic peptides have been widely reported to have therapeutic abilities in the treatment of cancer. This has been proven through in vitro and in vivo studies against breast, lung, liver, colon, and prostate cancers, among others. The multitude of data available in the literature supports the potential of cyclic peptides as anticancer agents. This review summarizes the findings from previously reported studies and discusses the different cyclic peptide compounds, the sources, and their modes of action as anticancer agents. The prospects and future of cyclic peptides will also be described to give an overview on the direction of cyclic peptide development for clinical applications.
Topics: Antineoplastic Agents; Humans; Neoplasms; Peptides; Peptides, Cyclic
PubMed: 35889301
DOI: 10.3390/molecules27144428 -
The New Phytologist May 2018Contents Summary 923 I. Introduction 923 II. Plant AEPs with macrocyclizing ability 924 III. Mechanism of macrocyclization by AEPs 925 IV. Conclusions 927... (Review)
Review
Contents Summary 923 I. Introduction 923 II. Plant AEPs with macrocyclizing ability 924 III. Mechanism of macrocyclization by AEPs 925 IV. Conclusions 927 Acknowledgements 927 References 927 SUMMARY: Plant asparaginyl endopeptidases (AEPs) are important for the post-translational processing of seed storage proteins via cleavage of precursor proteins. Some AEPs also function as peptide bond-makers during the biosynthesis of several unrelated classes of cyclic peptides, namely the kalata-type cyclic peptides, PawS-Derived Peptides and cyclic knottins. These three families of gene-encoded peptides have different evolutionary origins, but all have recruited AEPs for their maturation. In the last few years, the field has advanced rapidly, with the biochemical characterization of three plant AEPs capable of peptide macrocyclization, and insights have been gained from the first AEP crystal structures, albeit mammalian ones. Although the biochemical studies have improved our understanding of the mechanism of action, the focus now is to understand what changes in AEP sequence and structure enable some plant AEPs to perform macrocyclization reactions.
Topics: Amino Acid Sequence; Cyclization; Cysteine Endopeptidases; Models, Molecular; Peptides, Cyclic; Substrate Specificity
PubMed: 28322452
DOI: 10.1111/nph.14511 -
International Journal of Molecular... Oct 2020Using a random non-standard peptide integrated discovery system, we obtained cyclic peptides that bind to hepatocyte growth factor (HGF) or mesenchymal-epithelial... (Review)
Review
Using a random non-standard peptide integrated discovery system, we obtained cyclic peptides that bind to hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor. (MET) HGF-inhibitory peptide-8 (HiP-8) selectively bound to two-chain active HGF, but not to single-chain precursor HGF. HGF showed a dynamic change in its molecular shape in atomic force microscopy, but HiP-8 inhibited dynamic change in the molecular shape into a static status. The inhibition of the molecular dynamics of HGF by HiP-8 was associated with the loss of the ability to bind MET. HiP-8 could selectively detect active HGF in cancer tissues, and active HGF probed by HiP-8 showed co-localization with activated MET. Using HiP-8, cancer tissues with active HGF could be detected by positron emission tomography. HiP-8 seems to be applicable for the diagnosis and treatment of cancers. In contrast, based on the receptor dimerization as an essential process for activation, the cross-linking of the cyclic peptides that bind to the extracellular region of MET successfully generated an artificial ligand to MET. The synthetic MET agonists activated MET and exhibited biological activities which were indistinguishable from the effects of HGF. MET agonists composed of cyclic peptides can be manufactured by chemical synthesis but not recombinant protein expression, and thus are expected to be new biologics that are applicable to therapeutics and regenerative medicine.
Topics: Animals; Binding Sites; Biological Products; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Neoplasms; Peptides, Cyclic; Protein Binding; Proto-Oncogene Proteins c-met; Signal Transduction
PubMed: 33121208
DOI: 10.3390/ijms21217977 -
International Journal of Molecular... Oct 2022In recent years, cyclic peptides have attracted much attention due to their chemical and enzymatic stability, low toxicity, and easy modification. In general, the...
In recent years, cyclic peptides have attracted much attention due to their chemical and enzymatic stability, low toxicity, and easy modification. In general, the self-assembled nanostructures of cyclic peptides tend to form nanotubes in a cyclic stacking manner through hydrogen bonding. However, studies exploring other assembly strategies are scarce. In this context, we proposed a new assembly strategy based on cyclic peptides with covalent self-assembly. Here, cyclic peptide-(DPDPDP) was rationally designed and used as a building block to construct new assemblies. With cyclo-(DP) as the structural unit and 2,2'-diamino-N-methyldiethylamine as the linker, positively charged nanospheres ((CP)NS) based on cyclo-(DP) were successfully constructed by covalent self-assembly. We assessed their size and morphology by scanning electron microscopy (SEM), TEM, and DLS. (CP)NS were found to have a strong positive charge, so they could bind to siRNA through electrostatic interactions. Confocal microscopy analysis and cell viability assays showed that (CP)NS had high cellular internalization efficiency and low cytotoxicity. More importantly, real-time polymerase chain reaction (PCR) and flow cytometry analyses indicated that (CP)NS-siRNA complexes potently inhibited gene expression and promoted tumor cell apoptosis. These results suggest that (CP)NS may be a potential siRNA carrier for gene therapy.
Topics: RNA, Small Interfering; Peptides, Cyclic; Nanospheres; Nanotubes; Nanostructures
PubMed: 36292932
DOI: 10.3390/ijms232012071 -
The Biochemical Journal Mar 2017Macrocyclic compounds such as cyclic peptides have emerged as a new and exciting class of drug candidates for inhibition of intracellular protein-protein interactions,... (Review)
Review
Macrocyclic compounds such as cyclic peptides have emerged as a new and exciting class of drug candidates for inhibition of intracellular protein-protein interactions, which are challenging targets for conventional drug modalities (i.e. small molecules and proteins). Over the past decade, several complementary technologies have been developed to synthesize macrocycle libraries and screen them for binding to therapeutically relevant targets. Two different approaches have also been explored to increase the membrane permeability of cyclic peptides. In this review, we discuss these methods and their applications in the discovery of macrocyclic compounds against protein-protein interactions.
Topics: Animals; Biological Products; Biological Transport; Cell Membrane Permeability; Diffusion; Drug Discovery; Eukaryotic Cells; Humans; Inteins; Peptide Library; Peptides, Cyclic; Protein Binding; Protein Interaction Domains and Motifs; Proteins; Small Molecule Libraries
PubMed: 28298556
DOI: 10.1042/BCJ20160619 -
Journal of Chemical Theory and... Jun 2022An emerging class of therapeutic molecules are cyclic peptides with over 40 cyclic peptide drugs currently in clinical use. Their mode of action is, however, not fully...
An emerging class of therapeutic molecules are cyclic peptides with over 40 cyclic peptide drugs currently in clinical use. Their mode of action is, however, not fully understood, impeding rational drug design. Computational techniques could positively impact their design, but modeling them and their interactions remains challenging due to their cyclic nature and their flexibility. This study presents a step-by-step protocol for generating cyclic peptide conformations and docking them to their protein target using HADDOCK2.4. A dataset of 30 cyclic peptide-protein complexes was used to optimize both cyclization and docking protocols. It supports peptides cyclized via an N- and C-terminus peptide bond and/or a disulfide bond. An ensemble of cyclic peptide conformations is then used in HADDOCK to dock them onto their target protein using knowledge of the binding site on the protein side to drive the modeling. The presented protocol predicts at least one acceptable model according to the critical assessment of prediction of interaction criteria for each complex of the dataset when the top 10 HADDOCK-ranked single structures are considered (100% success rate top 10) both in the bound and unbound docking scenarios. Moreover, its performance in both bound and fully unbound docking is similar to the state-of-the-art software in the field, Autodock CrankPep. The presented cyclization and docking protocol should make HADDOCK a valuable tool for rational cyclic peptide-based drug design and high-throughput screening.
Topics: Cyclization; Molecular Docking Simulation; Peptides, Cyclic; Protein Binding; Protein Conformation; Proteins; Software
PubMed: 35652781
DOI: 10.1021/acs.jctc.2c00075 -
Angewandte Chemie (International Ed. in... Oct 2019Superior to linear peptides in biological activities, cyclic peptides are considered to have great potential as therapeutic agents. To identify cyclic-peptide ligands... (Review)
Review
Superior to linear peptides in biological activities, cyclic peptides are considered to have great potential as therapeutic agents. To identify cyclic-peptide ligands for therapeutic targets, phage-displayed peptide libraries in which cyclization is achieved by the covalent conjugation of cysteines have been widely used. To resolve drawbacks related to cysteine conjugation, we have invented a phage-display technique in which its displayed peptides are cyclized through a proximity-driven Michael addition reaction between a cysteine and an amber-codon-encoded N -acryloyl-lysine (AcrK). Using a randomized 6-mer library in which peptides were cyclized at two ends through a cysteine-AcrK linker, we demonstrated the successful selection of potent ligands for TEV protease and HDAC8. All selected cyclic peptide ligands showed 4- to 6-fold stronger affinity to their protein targets than their linear counterparts. We believe this approach will find broad applications in drug discovery.
Topics: Cyclization; Cysteine; Genetic Code; Humans; Ligands; Lysine; Peptide Library; Peptides, Cyclic
PubMed: 31398275
DOI: 10.1002/anie.201908713 -
Dalton Transactions (Cambridge, England... Feb 2014Cyclic pseudo-peptides derived from marine metabolites of the genus Lissoclinum bistratum and Lissoclinum patella have attracted scientific interest in the last two... (Review)
Review
Cyclic pseudo-peptides derived from marine metabolites of the genus Lissoclinum bistratum and Lissoclinum patella have attracted scientific interest in the last two decades. Their structural properties and solution dynamics have been analyzed in detail, elaborate synthetic procedures for the natural products and synthetic derivatives developed, the biosynthetic pathways studied and it now is possible to produce them biosynthetically. Initially, these macrocyclic ligands were studied due to their medicinal and pharmaceutical potential - some of the isolated cyclic pseudo-peptides show high cytotoxic and antiviral activity. A major focus in the last decade has been on their Cu(II) coordination chemistry, as a number of studies have indicated that dinuclear Cu(II) complexes of cyclic peptides may be involved in the ascidians' metabolism, and this is the focus of the present review.
Topics: Animals; Binding Sites; Coordination Complexes; Copper; Models, Molecular; Peptides, Cyclic; Urochordata
PubMed: 24202205
DOI: 10.1039/c3dt52664j