Human Insulin-like Peptide 5 (INSL5). Identification of a Simplified Version of Two-Chain Analog A13

Zhang, Xiaozhou; Bathgate, Ross A. D.; Hossain, Mohammed Akhter

doi:10.1021/acsmedchemlett.0c00435

Cited by 7 publications

(9 citation statements)

References 23 publications

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“…The study of structure-activity relationships (SARs) shows that the N-terminus and C-terminus of the Achain of insulin, as well as certain residues of the Bchain, are critical for receptor activation. 41,42 In the development of peptide drugs, another factor is agonism versus antagonistic action. 43 The market for peptide antagonists has been slower to develop, in part because of the high cost in the early days, but also because only a small amount of the antagonist (5-20%) is required for receptor activation.…”

Section: Parameters Of An Optimum Peptide Drug and Targetmentioning

confidence: 99%

Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate

et al. 2022

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In the last two decades, protein-protein interactions (PPIs) have been used as the main target for drug development. However, with larger or superficial binding sites, it has been extremely difficult to disrupt PPIs with small molecules. On the other hand, intracellular PPIs cannot be targeted by antibodies that cannot penetrate the cell membrane. Peptides that have a combination of conformational rigidity and flexibility can be used to target difficult binding interfaces with appropriate binding affinity and specificity. Since the introduction of insulin nearly a century ago, more than 80 peptide drugs have been approved to treat a variety of diseases. These include deadly diseases such as cancer and human immunodeficiency virus infection. It is also useful against diabetes, chronic pain, and osteoporosis. Today, more research is being done on these drugs as lessons learned from earlier approaches, which are still valid today, complement newer approaches such as peptide display libraries. At the same time, integrated genomics and peptide display libraries are new strategies that open new avenues for peptide drug discovery. The purpose of this review is to examine the problems in elucidating the peptide-protein recognition mechanism. This is important to develop peptide-based interventions that interfere with endogenous protein interactions. New approaches are being

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Section: Parameters Of An Optimum Peptide Drug and Targetmentioning

confidence: 99%

Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate

et al. 2022

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“…The first useful item in the toolbox is trimming off some N-terminal or C-terminal residues until a minimally active primary structure can be established (Figure 2A). This reductionistic approach is particularly efficacious in the case of TM peptides since, by removing (almost invariably hydrophobic) residues from the cognate TM sequence, water solubility is improved [70][71][72], while synthesis time and costs are considerably reduced. Another strategy to improve peptide solubility is PEGylation, i.e., attaching several polyethylene glycol (PEG) units to the peptide lead structure (Figure 2B).…”

Section: Tm Peptides: Challenges and Opportunities To Drug The Undrug...mentioning

confidence: 99%

Disrupting GPCR Complexes with Smart Drug-like Peptides

2022

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G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application.

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“…15−17 Because RXFP4 is a pseudogene in rats and is not detected in the mouse brain, the activation of RXFP4 by relaxin-3 is not a potential problem in probing RXFP3's functions in the rodent brain. 18,19 However, the activation of RXFP1 by relaxin-3 and an overlapping expression profile of RXFP3 and RXFP1 in the brain 12 make the selectivity for RXFP3 over RXFP1 critical for precise elucidation of RXFP3's functions.…”

Section: ■ Introductionmentioning

confidence: 99%

“…These relaxin-3 neurons were also activated following exposure to stressors (exogenous CRF or the inverse benzodiazepine agonist FG-7142) in a CRFR1-dependent manner . In rat models of anxiety and depression, the central administration of relaxin-3, as well as a synthetic RXFP3-specific agonist peptide, demonstrated anxiolytic- and antidepressant-like activities, suggesting a potential for RXFP3 agonists to treat anxiety- and depression-related disorders. − However, pharmacological validation of RXFP3 as a novel drug target has been hampered by the lack of potent, selective, and brain-penetrant small molecule agonists that can be administered peripherally. − …”

Section: Introductionmentioning

confidence: 99%

“…Relaxin-3 binds its endogenous receptor RXFP3 and inhibits forskolin (FSK)-stimulated cyclic adenosine monophosphate (cAMP) accumulation in Chinese hamster ovary (CHO) cells stably expressing human RXFP3 (hRXFP3) . Relaxin-3 also binds and activates receptors for H2 relaxin (RXFP1) and INSL5 (RXFP4), two members of the relaxin/insulin superfamily. − Because RXFP4 is a pseudogene in rats and is not detected in the mouse brain, the activation of RXFP4 by relaxin-3 is not a potential problem in probing RXFP3’s functions in the rodent brain. , However, the activation of RXFP1 by relaxin-3 and an overlapping expression profile of RXFP3 and RXFP1 in the brain make the selectivity for RXFP3 over RXFP1 critical for precise elucidation of RXFP3’s functions.…”

Section: Introductionmentioning

confidence: 99%

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Indole-Containing Amidinohydrazones as Nonpeptide, Dual RXFP3/4 Agonists: Synthesis, Structure–Activity Relationship, and Molecular Modeling Studies

et al. 2021

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The central relaxin-3/RXFP3 system plays important roles in stress responses, feeding, and motivation for reward. However, exploration of its therapeutic applications has been hampered by the lack of small molecule ligands and the cross-activation of RXFP1 in the brain and RXFP4 in the periphery. Herein, we report the first structure–activity relationship studies of a series of novel nonpeptide amidinohydrazone-based agonists, which were characterized by RXFP3 functional and radioligand binding assays. Several potent and efficacious RXFP3 agonists (e.g., 10d) were identified with EC50 values <10 nM. These compounds also had high potency at RXFP4 but no agonist activity at RXFP1, demonstrating > 100-fold selectivity for RXFP3/4 over RXFP1. In vitro ADME and pharmacokinetic assessments revealed that the amidinohydrazone derivatives may have limited brain permeability. Collectively, our findings provide the basis for further optimization of lead compounds to develop a suitable agonist to probe RXFP3 functions in the brain.

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Human Insulin-like Peptide 5 (INSL5). Identification of a Simplified Version of Two-Chain Analog A13

Cited by 7 publications

References 23 publications

Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate

Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate

Disrupting GPCR Complexes with Smart Drug-like Peptides

Indole-Containing Amidinohydrazones as Nonpeptide, Dual RXFP3/4 Agonists: Synthesis, Structure–Activity Relationship, and Molecular Modeling Studies

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