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Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety

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Abstract

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic arginine-rich peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic arginine-rich peptide, protamine, which has been in clinical use for over 70 years to reverse the anticoagulant effects of heparin and as an excipient in certain insulin preparations, is well established. In addition, the poly-arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic arginine-rich peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of ischaemic stroke, haemorrhagic stroke and Alzheimer’s disease, respectively. Based on the available clinical data, cationic arginine-rich peptides as a group appear to be safe when administered at therapeutic doses by a slow intravenous infusion. While protamine, owing to its isolation from salmon milt and homology with human sperm protamine, can trigger anaphylactic and anaphylactoid reactions in a small proportion of patients previously exposed to the peptide (e.g. diabetic patients), who are allergic to fish or have undergone a vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-protamine cationic arginine-rich peptides.

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Authors and Affiliations

  1. Perron Institute for Neurological and Translational Sciences, First Floor, RR Block, QEII Medical Centre, Nedlands, WA, Australia

    Adam B. Edwards, Frank L. Mastaglia, Neville W. Knuckey & Bruno P. Meloni

  2. Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA, Australia

    Adam B. Edwards, Neville W. Knuckey & Bruno P. Meloni

  3. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, Australia

    Adam B. Edwards, Frank L. Mastaglia, Neville W. Knuckey & Bruno P. Meloni

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This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Neville W. Knuckey and Bruno P. Meloni are named inventors on several patents for the use of CARPs as therapeutic agents. In addition, Neville W. Knuckey, Bruno P. Meloni and Adam B. Edwards are shareholders in Argenica Therapeutics, which is a company developing R18 as a stroke therapeutic. Frank L. Mastaglia has no conflicts of interest that are directly relevant to the content of this article.

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Edwards, A.B., Mastaglia, F.L., Knuckey, N.W. et al. Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety. Drug Saf 43, 957–969 (2020). https://doi.org/10.1007/s40264-020-00962-z

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