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NAP Alpha-Aminoisobutyric Acid (IsoNAP)

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Abstract

We set out to identify NAP (davunetide) analogs, providing neuroprotection and reducing tau pathology, specifically addressing protection against protein misfolding. NAP (NAPVSIPQ, intranasal formulation AL-108) is a drug candidate that (1) had a statistically significant impact on two measures, namely digit span and delayed-match-to-sample, tests of verbal recall and visual working memory, respectively, in patient population of mild cognitive impairment [preceding Alzheimer’s disease (AD)] and (2) protected functional activities of daily living in schizophrenia patients. Previous preclinical studies have shown that stabilization of NAP by replacement of all l-amino acids by d-amino acids resulted in an active peptide, d-NAP. Other NAP mimetics are now explored. A new NAP analog was designed that included replacement of the proline residues by alpha-aminoisobutyric acid to enhance β-sheet breaker characteristics, thereby reducing protein misfolding. Three lines of investigations were chosen: (1) protection against the AD-associated amyloid β (1-42), Aβ1-42, peptide toxicity in cell cultures; (2) inhibition of AD-associated tau aggregation in vitro; and (3) cognitive protection in a mouse model of deficiencies of the NAP parent protein, activity-dependent neuroprotective protein (ADNP), exhibiting tau pathology and neurodegeneration. NAP alpha-aminoisobutyric acid (IsoNAP) protected neurons against AD-associated Aβ1-42-toxicity, inhibited the aggregation of the tau-derived peptide VQIVYK (important for the aggregation of tau into paired helical filaments, which form the tangles found in AD and related disorders), and protected cognitive functions in a model of ADNP deficiency. With AD being the major tauopathy, novel NAP derivatives that reduce tauopathy and provide neuroprotection as well as cognitive protection are of scientific and clinical interest.

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Acknowledgments

Professor Gozes’ laboratory is supported by the AMN Foundation, CFTAU Montreal Circle of Friends and the Adams family, Adams Super Center for Brain Studies, and Lily and Avraham Gildor Chair for the Investigation of Growth Factors at Tel Aviv University. Initial studies in this research were also partially supported by Allon Therapeutics Inc. Yulie Schirer and Anat Idan-Feldman performed this work as part of their graduate studies in the Dr. Miriam and Sheldon G. Adelson Graduate School of Medicine associated with the Sackler Faculty of Medicine at Tel Aviv University. Merav David was an undergraduate student at the combined medicine–biology program of Tel Aviv University. Professor Gozes is currently a Humboldt Award recipient and a fellow at the Hanse-Wissenschaftenskolleg, Germany. IsoNAP is under patent protection, Ramot at Tel Aviv University.

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Authors and Affiliations

  1. The Adams Super Center for Brain Studies and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel

    Illana Gozes, Yulie Schirer, Anat Idan-Feldman, Merav David & Sharon Furman-Assaf

  2. The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Tel Aviv University, Tel Aviv, 69978, Israel

    Illana Gozes, Yulie Schirer, Anat Idan-Feldman, Merav David & Sharon Furman-Assaf

  3. Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Illana Gozes, Yulie Schirer, Anat Idan-Feldman, Merav David & Sharon Furman-Assaf

  4. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Illana Gozes, Yulie Schirer, Anat Idan-Feldman, Merav David & Sharon Furman-Assaf

  5. The Edersheim-Levie-Gitter fMRI Institute, Tel Aviv University, Tel Aviv, Israel

    Illana Gozes

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  1. Illana Gozes
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Correspondence to Illana Gozes.

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Gozes, I., Schirer, Y., Idan-Feldman, A. et al. NAP Alpha-Aminoisobutyric Acid (IsoNAP). J Mol Neurosci 52, 1–9 (2014). https://doi.org/10.1007/s12031-013-0103-8

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  • DOI: https://doi.org/10.1007/s12031-013-0103-8

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