Tyr1-ψ[(Z)CF═CH]-Gly2 Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin

Altman, Ryan A.; Sharma, Krishna K.; Rajewski, Lian; Toren, Paul; Baltezor, Michael; Pal, M.; Karad, Somnath Narayan

doi:10.1021/acschemneuro.8b00085

Cited by 36 publications

(23 citation statements)

References 54 publications

(103 reference statements)

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“…Moreover, in the specific case of GPCR complexes, CPPs can also determine the trajectory of the peptide disruptor into the membrane [80]. Peptide backbone modification is also an important and widely used approach to improve bioavailability [83,84]. Still another strategy to increase target affinity and cell uptake, as well as to protect against proteolytic degradation, involves stapling, whereby a synthetic brace (staple) introduced between two preestablished sites in the sequence helps to lock the peptide into a specific secondary structure (Figure 2F), thus reducing conformational entropy [85][86][87].…”

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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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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“…Later, Altman et al . reported that Leu‐enkephalin derivatives Tyr 1 ‐ψ[(Z)CF=CH]‐Gly 2 with the second amide bond modified by the fluoroalkene moiety showed improved distribution and metabolic properties [82] …”

Section: Peptide Backbone Modifications and Solid‐phase Synthesis Tec...mentioning

confidence: 99%

Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications

2021

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Peptidomimetics are a class of compounds with promising pharmacological properties. Peptidomimetics reduce limitations of peptides including low bioavailability, poor stability, and poor cell‐permeability. Peptide backbone modifications are a frequently used manipulation to reach desirable properties of the peptide molecules. The development of accessible synthetic methodologies plays an important role in peptidomimetic progress. Synthesis of peptidomimetics proceeds via solution and solid‐phase synthesis strategies. Solid‐phase organic synthesis serves as a powerful tool for the preparation of peptidomimetic molecules, thus, numerous strategies have been developed over the years. In this review, we discuss solid‐phase synthetic approaches for peptide backbone modifications that were presented in the last two decades.

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“…One of the most viable alternatives to small molecule painkillers is to develop native endogenic peptide pain relievers with enhanced drug-like properties. Various strategies have been developed over the years to produce stable enkephalin and endorphin mimetics (Karad et al, 2017 ; Altman et al, 2018 ; Harris et al, 2019 ). These short peptides contained all the essential pharmacophores of the parent peptide that proved crucial for bioactivity.…”

Section: Introductionmentioning

confidence: 99%

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Talhami

Swed

Hess³

et al. 2020

Front. Chem.

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Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6) , which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6) , we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6) .

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Tyr¹-ψ[(Z)CF═CH]-Gly² Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin

Cited by 36 publications

References 54 publications

Disrupting GPCR Complexes with Smart Drug-like Peptides

Disrupting GPCR Complexes with Smart Drug-like Peptides

Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

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