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Background and Purpose: In light of the opioid epidemic, physicians are increasingly prescribing non-opioid analgesics to surgical patients. Transient receptor potential vanilloid 1 (TRPV1) inhibitors are potentially alternative pain therapeutics for surgery. Here, we examined in rodents whether the cardioprotection conferred by two common procedures during surgery, a laparotomy or morphine delivery, is mediated by the TRPV1 channel. We further tested whether an experimental analgesic peptide (known as P5) targeted against the TRPV1 C-terminus region interferes with laparotomy- or morphine-induced cardioprotection.Experimental Approach: Male Sprague-Dawley rats were subjected to 30 min coronary occlusion followed by 120 min reperfusion. Before ischaemia, a laparotomy with or without capsaicin application (0.1% cream, a TRPV1 activator) was performed. Additional rats were given morphine (0.3 mg·kg-1 ) with or without capsaicin. In addition, capsazepine (3 mg·kg-1 , a classical TRPV1 inhibitor), or P5 (3 mg·kg-1 , a peptide analgesic and TRPV1 inhibitor), was given either alone or prior to a laparotomy or morphine administration. Myocardial infarct size was determined.Key Results: A laparotomy, in addition to combining a laparotomy with capsaicin cream, reduced infarct size versus control. Morphine, in addition to combining morphine administration with capsaicin cream, also reduced infarct size versus control. When TRPV1 inhibitors capsazepine or P5 were given, either TRPV1 inhibitor abolished the infarct size reduction mediated by a laparotomy or morphine.Conclusions and Implications: Inhibiting the TRPV1 channel blocks laparotomy- or morphine-induced cardioprotection. Impaired organ protection may be a potential pitfall of using TRPV1 inhibitors for pain control. [ABSTRACT FROM AUTHOR]

Most protein kinases phosphorylate multiple substrates, each of which induces different and sometimes opposing functions. Determining the role of phosphorylation of each substrate following a specific stimulus is challenging but is essential to elucidate the role of that substrate in the signaling event. Here we describe a rational approach to identify inhibitors of delta protein kinase C (δPKC), each inhibiting the phosphorylation of only one of δPKC′s substrates. δPKC regulates many signaling events and we hypothesized that a docking inhibitor of a given substrate to δPKC should selectively abrogate the phosphorylation of only that substrate, without affecting the phosphorylation of the other δPKC substrates. Here we report the development of selective inhibitors of three δPKC substrates (in vitro Kd≈3 n m); two greatly reduced ischemia-induced cardiac injury with an IC50 of ≈200 n m and the third had no effect, indicating that its respective substrate phosphorylation by δPKC has no role in the response to cardiac ischemia and reperfusion. The three inhibitors are highly specific; even at 1 μ m, the phosphorylation of other δPKC protein substrates was unaffected. The rationale we describe is likely applicable for the development of other substrate-specific inhibitors as well. [ABSTRACT FROM AUTHOR]

Phosphopeptides are important tools for studying intracellular signal transduction events in vitro and in vivo and are also potential drugs due to their direct competition with phosphoprotein recognition elements. Cyclization has been demonstrated to improve peptide selectivity, metabolic stability, and bioavailability. However, cyclic phosphopeptide synthesis may not be straightforward due to the sterically hindered phosphorylated side-chain amino acid derivatives. One option to overcome this hurdle is to use microwaveassisted synthesis, which has been shown to increase efficiency and reduce synthesis time. Herein, a detailed protocol is provided for synthesizing cyclic phosphopeptides using automated microwave. The overall synthesis duration was reduced and yields increased compared with a manual conventional method. This method provides a general, fast and facile way to synthesize cyclic peptides, demonstrating the synthesis of cyclic phosphorylated peptides which are known to be among the most challenging to produce. [ABSTRACT FROM AUTHOR]

Photoaffinity labeling is used to covalently attach ligands to macromolecules to determine their spatial arrangement and structure. Benzophenone (BP) groups are widely used for covalent photoaffinity labeling and for probing protein interactions. We developed bifunctional BP photoactivatable derivatives using three different general chemical approaches. In addition to the photoaffinity reactivity of the BP, these derivatives contain an additional group: A radioactive tracer for biological studies, or an N-ethylmaleimide group as an additional crosslinker, or a biotin group to be used during purification and characterization of probe-protein complexes using the high-affinity biotin-avidin interaction. A model series of photoaffinity labeling probes was synthesized based on the arbutin ligand. These compounds can be used as probes to study the arbutin binding site of microbial β-glucoside transporters by photolabeling residues in its vicinity. The second functionality provides additional options for studying proteins and binding sites. The probes were developed using different methodologies: (i) a diazotation reaction; (ii) protecting group methodology; and (iii) solid-phase synthesis. These procedures are general and provide a simple and versatile approach for synthesizing bifunctional BP ligands, as demonstrated here on arbutin. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 526-536, 2008. This article was originally published online as an accepted preprint. The 'Published Online' date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [ABSTRACT FROM AUTHOR]

A diagram is presented which explains the cardioprotective activity of peptides which are measured in whole hearts subjected to simulated myocardial infraction stained in triphenyltetrazolium chloride solution.

A correction to the article "Engineered Substrate-Specific Delta PKCAntagonists to Enhance Cardiac Therapeutics" that was published in the issue numbered DOI: 10.1002/anie.201605429 and 2016, 55 is presented.