Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases

Daryl Ariawan; Kanishka  P. M. Pushpitha; Ali El-Omar; Julia van der Hoven; Sian Genoud; Holly Stefen; Thomas Fath; Janet van Eersel; Lars M. Ittner; Ole Tietz

doi:10.1039/D4RA05040A

Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases

Daryl Ariawan, Kanishka P. M. Pushpitha, Ali El-Omar, Julia van der Hoven, Sian Genoud, Holly Stefen, Thomas Fath, Janet van Eersel, Lars M. Ittner, Ole Tietz

Macquarie Medical School

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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Abstract

Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein–protein interactions (PPIs). Nerinetide has recently emerged as a promising therapeutic for the treatment of ischemic stroke and Alzheimer's Disease (AD). The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein–protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry. In this study, we deconstruct the nerinetide sequence and study the relationship between plasma stability, intraneuronal delivery and drug efficacy to provide design guidelines for the development of next generation, peptidic PPI inhibitors to treat neurodegenerative diseases.

Original language	English
Pages (from-to)	34637-34642
Number of pages	6
Journal	RSC Advances
Volume	14
Issue number	47
DOIs	https://doi.org/10.1039/D4RA05040A
Publication status	Published - 30 Oct 2024

Bibliographical note

Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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10.1039/D4RA05040ALicence: CC BY-NC

Publisher version (open access)Final published version, 851 KBLicence: CC BY-NC

Cite this

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title = "Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases",

abstract = "Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein–protein interactions (PPIs). Nerinetide has recently emerged as a promising therapeutic for the treatment of ischemic stroke and Alzheimer's Disease (AD). The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein–protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry. In this study, we deconstruct the nerinetide sequence and study the relationship between plasma stability, intraneuronal delivery and drug efficacy to provide design guidelines for the development of next generation, peptidic PPI inhibitors to treat neurodegenerative diseases.",

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note = "Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

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doi = "10.1039/D4RA05040A",

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T1 - Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases

AU - Ariawan, Daryl

AU - Pushpitha, Kanishka P. M.

AU - El-Omar, Ali

AU - van der Hoven, Julia

AU - Genoud, Sian

AU - Stefen, Holly

AU - Fath, Thomas

AU - van Eersel, Janet

AU - Ittner, Lars M.

AU - Tietz, Ole

N1 - Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2024/10/30

Y1 - 2024/10/30

N2 - Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein–protein interactions (PPIs). Nerinetide has recently emerged as a promising therapeutic for the treatment of ischemic stroke and Alzheimer's Disease (AD). The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein–protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry. In this study, we deconstruct the nerinetide sequence and study the relationship between plasma stability, intraneuronal delivery and drug efficacy to provide design guidelines for the development of next generation, peptidic PPI inhibitors to treat neurodegenerative diseases.

AB - Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein–protein interactions (PPIs). Nerinetide has recently emerged as a promising therapeutic for the treatment of ischemic stroke and Alzheimer's Disease (AD). The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein–protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry. In this study, we deconstruct the nerinetide sequence and study the relationship between plasma stability, intraneuronal delivery and drug efficacy to provide design guidelines for the development of next generation, peptidic PPI inhibitors to treat neurodegenerative diseases.

UR - https://www.scopus.com/pages/publications/85208275302

UR - https://purl.org/au-research/grants/nhmrc/2000660

UR - https://purl.org/au-research/grants/arc/DP240101654

UR - https://purl.org/au-research/grants/nhmrc/2029740

UR - https://purl.org/au-research/grants/nhmrc/2027621

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DO - 10.1039/D4RA05040A

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SN - 2046-2069

VL - 14

SP - 34637

EP - 34642

JO - RSC Advances

JF - RSC Advances

IS - 47

ER -

Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases

Abstract

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DP24: Transcriptional and translational regulation of the neuronal protein tau

IDEAS 23: Development of next-generation gene therapy vectors for the treatment of epilepsy

IDEAS 23: New biological drugs to treat Alzheimer's disease

Cite this

Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases

Abstract

Bibliographical note

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Projects

DP24: Transcriptional and translational regulation of the neuronal protein tau

IDEAS 23: Development of next-generation gene therapy vectors for the treatment of epilepsy

IDEAS 23: New biological drugs to treat Alzheimer's disease

Cite this