Natural endogenously occurring peptides exhibit desirable medicinal properties, but are often limited in application by rapid proteolysis and inadequate membrane permeability. However, editing naturally occurring peptide sequences to develop peptidomimetic analogs created a promising class of therapeutics that can augment or inhibit molecular interactions. Here, we discuss a variety of chemical modifications, including L to D isomerization, cyclization, and unnatural amino acid substitution, as well as design strategies, such as attachment to cell-penetrating peptides, which are used to develop peptidomimetics. We also provide examples of approved peptidomimetics and discuss several compounds in clinical trials.

BACKGROUND AND PURPOSEIn 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 APPROACHMale 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 RESULTSA 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 IMPLICATIONSInhibiting the TRPV1 channel blocks laparotomy-or morphine-induced cardioprotection. Impaired organ protection may be a potential pitfall of using TRPV1 inhibitors for pain control.

Background: Recent evidence suggests that cross talk exists between cellular pathways important for pain signaling and ischemia-reperfusion injury. Here, the authors address whether the transient receptor potential ankyrin 1 (TRPA1) channel, important in pain signaling, is present in cardiac myocytes and regulates cardiac ischemia-reperfusion injury.Methods: For biochemical analysis of TRPA1, techniques including quantitative polymerase chain reaction, Western blot, and immunofluorescence were used. To determine how TRPA1 mediates cellular injury, the authors used an in vivo model of rat cardiac ischemia-reperfusion injury and adult rat-isolated cardiac myocytes subjected to hypoxia-reoxygenation.Results: The authors' biochemical analysis indicates that TRPA1 is within the cardiac myocytes. Further, using a rat in vivo model of cardiac injury, the TRPA1 activators ASP 7663 and optovin reduce myocardial injury (45 +/- 5%* and 44 +/- 8%,* respectively, vs. control, 66 +/- 6% infarct size/area at risk; n = 6 per group; mean +/- SD; * P < 0.001). TRPA1 inhibition also blocked the infarct size-sparing effects of morphine. In isolated cardiac myocytes, the TRPA1 activators ASP 7663 and optovin reduce cardiac myocyte cell death when given during reoxygenation (20 +/- 3%* and 22 +/- 4%* vs. 36 +/- 3%; percentage of dead cells per field, n = 6 per group; mean +/- SD; *P < 0.05). For a rat in vivo model of cardiac injury, the infarct size-sparing effect of TRPA1 activators also occurs during reperfusion.Conclusions: The authors' data suggest that TRPA1 is present within the cardiac myocytes and is important in regulating myocardial reperfusion injury. The presence of TRPA1 within the cardiac myocytes may potentially explain why certain pain relievers that can block TRPA1 activation, such as cyclooxygenase-2 inhibitors or some nonsteroidal antiinflammatory drugs, could be associated with cardiovascular risk.

Opioids reduce injury from myocardial ischemia-reperfusion in humans. In experimental models, this mechanism involves GSK3 beta inhibition. HSP90 regulates mitochondrial protein import, with GSK3 beta inhibition increasing HSP90 mitochondrial content. Therefore, we determined whether morphine-induced cardioprotection is mediated by HSP90 and if the protective effect is downstream of GSK3 beta inhibition. Male Sprague-Dawley rats, aged 8-10 weeks, were subjected to an in vivo myocardial ischemia-reperfusion injury protocol involving 30 minutes of ischemia followed by 2 hours of reperfusion. Hemodynamics were continually monitored and myocardial infarct size determined. Rats received morphine (0.3 mg/kg), the GSK3 beta inhibitor, SB216763(0.6mg/kg), or saline, 10 minutes prior to ischemia. Some rats received selective HSP90 inhibitors, radicicol (0.3mg/kg), or deoxyspergualin (DSG, 0.6mg/kg) alone or 5 minutes prior to morphine or SB216763. Morphine reduced myocardial infarct size when compared to control (42 +/- 2% versus 60 +/- 1%). This protection was abolished by prior treatment of radicicol or DSG (59 +/- 1%, 56 +/- 2%). GSK3 beta inhibition also reduced myocardial infarct size (41 +/- 2%) with HSP90 inhibition by radicicol or DSG partially inhibiting SB216763-induced infarct size reduction (54 +/- 3%, 47 +/- 1%, resp.). These data suggest that opioid-induced cardioprotection is mediated by HSP90. Part of this protection afforded by HSP90 is downstream of GSK3 beta, potentially via the HSP-TOM mitochondrial import pathway.