Harnessing cyclotides to design and develop novel peptide GPCR ligands

Muratspahić, Edin; Koehbach, Johannes; Gruber, Christian W.; Craik, David J.

doi:10.1039/d0cb00062k

Cited by 24 publications

(36 citation statements)

References 129 publications

(241 reference statements)

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“…Pasireotide is a hexapeptide with headto-tail cyclized. Pasireotide binds with higher affinity to Somatostatin Receptor 1 (SSTR1, 30-fold), SSTR3 (5-fold), and SSTR5 (39-fold) and with the same affinity to SSTR2 when compared with octreotide, a higher affinity to SSTR1 (19-fold), SSTR3 (9-fold), and SSTR5 (106-fold) and the same affinity to SST2R (2fold) when compared with lanreotide [18,19]. Pasireotide was approved for Cushing's disease by EMA [74] and FDA in 2012 [75].…”

Section: Ziconotide (3 Table 2 Andmentioning

confidence: 99%

“…However, cyclization makes the development of cyclic peptide drugs more challenging than the development of linear peptides [4,16]. The majority of approved cyclic peptides are engineered from natural analogs by keeping the overall cyclic peptide structure to maintain affinity to the target protein [17,18]. Canonical peptide chains are conventionally cyclized by head-tail amidation, disulfide bond formation between cysteines, sidechain amine to C-terminus carboxyl group and sidechain carboxyl group to N-terminus amidations [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Cyclic peptide drugs approved in the last two decades (2001–2021)

2022

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Section: Ziconotide (3 Table 2 Andmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyclic peptide drugs approved in the last two decades (2001–2021)

2022

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“…In recent years, numerous studies have unveiled the potential of nature-derived peptides as an extensive source for GPCR ligand design 22 , 23 . These peptide GPCR ligands have been isolated from various organisms including plants 22 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of the cyclotide caripe 11 as a ligand of the cholecystokinin-2 receptor

Taghizadeh

Retzl

Muratspahić

et al. 2022

Sci Rep

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The cholecystokinin-2 receptor (CCK2R) is a G protein-coupled receptor (GPCR) that is expressed in peripheral tissues and the central nervous system and constitutes a promising target for drug development in several diseases, such as gastrointestinal cancer. The search for ligands of this receptor over the past years mainly resulted in the discovery of a set of distinct synthetic small molecule chemicals. Here, we carried out a pharmacological screening of cyclotide-containing plant extracts using HEK293 cells transiently-expressing mouse CCK2R, and inositol phosphate (IP1) production as a readout. Our data demonstrated that cyclotide-enriched plant extracts from Oldenlandia affinis, Viola tricolor and Carapichea ipecacuanha activate the CCK2R as measured by the production of IP1. These findings prompted the isolation of a representative cyclotide, namely caripe 11 from C. ipecacuanha for detailed pharmacological analysis. Caripe 11 is a partial agonist of the CCK2R (Emax = 71%) with a moderate potency of 8.5 µM, in comparison to the endogenous full agonist cholecystokinin-8 (CCK-8; EC50 = 11.5 nM). The partial agonism of caripe 11 is further characterized by an increase on basal activity (at low concentrations) and a dextral-shift of the potency of CCK-8 (at higher concentrations) following its co-incubation with the cyclotide. Therefore, cyclotides such as caripe 11 may be explored in the future for the design and development of cyclotide-based ligands or imaging probes targeting the CCK2R and related peptide GPCRs.

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“… 4 Notably, plant-derived peptides offer the potential to design and develop potent GPCR ligands with improved pharmacological properties. 5 Due to their exceptional stability and plasticity to accommodate sequence variations without affecting the overall three-dimensional structure, cyclic cystine-rich peptides such as cyclotides have been successfully utilized in molecular “grafting” applications. For instance, this approach has led to the design of potent, stable, and selective peptide ligands for the melanocortin 4 receptor, 6 bradykinin B1 receptor, 7 CXC-motif-chemokine receptor 4, 8 and MAS 1 receptor.…”

Section: Introductionmentioning

confidence: 99%

Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain

et al. 2021

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The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower ( Helianthus annuus ) preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.

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Harnessing cyclotides to design and develop novel peptide GPCR ligands

Abstract: Cyclotides are plant-derived cyclic peptides that have emerged as promising scaffold molecules for designing peptide-based therapeutics. Cyclotide engineering may lead to the development of novel ligands of G protein-coupled receptors with improved pharmacological properties.

Cited by 24 publications

References 129 publications

Cyclic peptide drugs approved in the last two decades (2001–2021)

Cyclic peptide drugs approved in the last two decades (2001–2021)

Discovery of the cyclotide caripe 11 as a ligand of the cholecystokinin-2 receptor

Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain

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