Emerging cytoprotective peptide therapies for stroke

Meloni, Bruno P.; Blacker, David; Mastaglia, Frank; Knuckey, Neville W.

doi:10.1080/14737175.2020.1788390

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…Among them, NA-1 , originally named TAT-NR2B9, is a lead compound being developed by NoNO for the treatment of stroke, traumatic brain injuries and subarachnoid hemorrhage and is currently in Phase 3 clinical trial. NA-1 is a 20-mer peptide consisting in a sequence (KLSSIESDV) derived from the intracellular terminal carboxylic region of the N-methyl-D-aspartate (NMDA) receptor NR2B subunit protein, fused to the cationic arginine-rich cell penetrating peptide TAT (YGRKKRRQRRR), which facilitates the passage across the blood brain barrier ( Ballarin and Tymianski 2018 ; Meloni et al, 2020 ). The NR2B9 9-mer peptide was selected to inhibit the postsynaptic density protein-95 (PSD95) adaptor protein, which binds to the NR2B subunit, and thereby blocks downstream cell signalling associated with overstimulation of the NMDA receptor.…”

Section: Cardiovascular System and Hypertensionmentioning

confidence: 99%

“…This peptide is in Phase 2 for the treatment of hemorrhagic stroke and intracerebral hemorrhage. CN-105 has been developed based on the amino acids present in the parent neuroprotective peptide COG133, comprising the heparin binding and LDL receptor binding domains within the apoE ( Meloni et al, 2020 ). ApoE is a multifunctional 299-mer protein that reduces neuroinflammation and mediates adaptive responses following ischemic and traumatic brain injury.…”

Section: Cardiovascular System and Hypertensionmentioning

confidence: 99%

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Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

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Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.

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Section: Cardiovascular System and Hypertensionmentioning

confidence: 99%

Section: Cardiovascular System and Hypertensionmentioning

confidence: 99%

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

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show abstract

“…The cationic arginine-rich peptides (CARPs) poly-arginine-18 (R18; 18-mer of L-enantiomer arginine; net charge + 18), its D-enantiomer (R18D) and NA-1 (also known as nerinetide or TAT-NR2B9c; net charge + 7) represent emerging neuroprotective therapies for the acute treatment of ischaemic stroke, especially prior to thrombolysis and endovascular thrombectomy [ 1 ]. This group of compounds possess potent neuroprotective properties, with peptide arginine content and peptide positive charge critical for neuroprotection [ 2 – 4 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of poly-arginine peptides R18D and R18 on alteplase and tenecteplase thrombolysis in vitro, and neuroprotective stability to proteolysis

Meloni

Blacker

Edwards

et al. 2022

J Thromb Thrombolysis

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The poly-arginine peptides R18D and R18 represent novel potential neuroprotective treatments for acute ischaemic stroke. Here we examined whether R18D and R18 had any significant effects on the thrombolytic activity of alteplase (tPA) and tenecteplase (TNK) on clots formed from whole blood in an in vitro thrombolysis plate assay. R18D and R18 were examined at concentrations of 0.25, 0.5, 1, 2, 4, 8 and 16 µM during the 1-h thrombolytic assay. We also included the well-characterised neuroprotective NA-1 peptide as a control. R18D, R18 and NA-1 all reduced tPA or TNK percentage clot lysis by 0–9.35%, 0–3.44% and 0–4.8%, respectively. R18D, R18 and NA-1 had a modest and variable effect on the lag time, increasing the time to the commencement of thrombolysis by 0–9.9 min, 0–5.53 min and 0–7.16 min, respectively. Lastly, R18 and NA-1 appeared to increase the maximal activity of the thrombolysis reaction. In addition, the in vitro anti-excitotoxic neuroprotective efficacy of R18D and R18 was not affected by pre-incubation for 1–2 h or overnight with tPA or TNK, whereas only R18D retained high anti-excitotoxic neuroprotective efficacy when pre-incubated in a synthetic trypsin (TrypLE Express). The present in vitro findings suggest that neither R18D or R18 when co-administered with the thrombolytic inducing agents tPA or TNK are likely to have a significant impact when used clinically during clot thrombolysis and confirm the superior proteolytic stability of the R18D peptide.

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Therapeutic potential of ApoE-mimetic peptides in CNS disorders: Current perspective

Ahmed

Pande

Sharma

2022

Experimental Neurology

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Emerging cytoprotective peptide therapies for stroke

Cited by 5 publications

References 36 publications

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Impact of poly-arginine peptides R18D and R18 on alteplase and tenecteplase thrombolysis in vitro, and neuroprotective stability to proteolysis

Therapeutic potential of ApoE-mimetic peptides in CNS disorders: Current perspective

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