Dihexa

Last updated
Dihexa
Dihexa.svg
Clinical data
Other namesN-(1-Oxohexyl)-l-tyrosyl-N-(6-amino-6-oxohexyl)-l-isoleucinamide
Identifiers
  • 6-[(2S,3S)-2-[(2S)-2-hexanamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]hexanamide
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C27H44N4O5
Molar mass 504.672 g·mol−1
3D model (JSmol)
  • CCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCCCCCC(N)=O
  • InChI=1S/C27H44N4O5/c1-4-6-8-12-24(34)30-22(18-20-13-15-21(32)16-14-20)26(35)31-25(19(3)5-2)27(36)29-17-10-7-9-11-23(28)33/h13-16,19,22,25,32H,4-12,17-18H2,1-3H3,(H2,28,33)(H,29,36)(H,30,34)(H,31,35)/t19-,22-,25-/m0/s1
  • Key:XEUVNVNAVKZSPT-JTJYXVOQSA-N

Dihexa (developmental code PNB-0408; also known as N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is an oligopeptide drug derived from angiotensin IV that binds with high affinity to hepatocyte growth factor (HGF) and potentiates its activity at its receptor, c-Met. The compound has been found to potently improve cognitive function in animal models of Alzheimer's disease-like mental impairment. [1] [2] [3] [4] [5] [6] [7] [8] In an assay of neurotrophic activity, dihexa was found to be seven orders of magnitude more potent than brain-derived neurotrophic factor. [9]

According to a patent, "Short duration safety studies with dihexa have uncovered no apparent toxicity. Of particular note is a lack of neoplastic induction [ citation needed ], since c-Met is recognized as an oncogene. This is unsurprising since oncogenesis requires multiple mutations including both oncogene induction and tumor suppressor attenuation." [10] [ citation needed ]

History

Dihexa was developed by Joseph Harding and his team at Washington State University. [11] Later developments were done by M3 Biotechnology, a company founded to commercialize dihexa. [12]

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Angiotensin</span> Group of peptide hormones in mammals

Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.

The angiotensin II receptors, (ATR1) and (ATR2), are a class of G protein-coupled receptors with angiotensin II as their ligands. They are important in the renin–angiotensin system: they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II.

<span class="mw-page-title-main">Hepatocyte growth factor receptor</span> Mammalian protein found in Homo sapiens

Hepatocyte growth factor receptor is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.

Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

<span class="mw-page-title-main">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.

<span class="mw-page-title-main">Tropomyosin receptor kinase B</span> Protein and coding gene in humans

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The standard pronunciation for this protein is "track bee".

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

Neurturin (NRTN) is a protein that is encoded in humans by the NRTN gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the transforming growth factor beta (TGF-beta) subfamily along with its homologs persephin, artemin, and GDNF. It shares a 42% similarity in amino acid sequence with mature GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial settings for the potential treatment of neurodegenerative diseases, specifically Parkinson's disease.

<span class="mw-page-title-main">Hepatocyte growth factor</span> Mammalian protein found in Homo sapiens

Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing.

<span class="mw-page-title-main">HNF1A</span> Protein-coding gene in the species Homo sapiens

HNF1 homeobox A, also known as HNF1A, is a human gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Mutations in the HNF1A gene have been known to cause diabetes. The HNF1A gene also contains a SNP associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">SPINT1</span> Protein-coding gene in the species Homo sapiens

Kunitz-type protease inhibitor 1 is an enzyme that in humans is encoded by the SPINT1 gene.

<span class="mw-page-title-main">HGFAC</span> Protein-coding gene in humans

Hepatocyte growth factor activator is a protein that in humans is encoded by the HGFAC gene.

<span class="mw-page-title-main">LY-503430</span> Chemical compound

LY-503430 is an AMPA receptor positive allosteric modulator developed by Eli Lilly.

c-Met inhibitors are a class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase, the receptor of hepatocyte growth factor/scatter factor (HGF/SF). These inhibitors may have therapeutic application in the treatment of various types of cancers.

Translational neuroscience is the field of study which applies neuroscience research to translate or develop into clinical applications and novel therapies for nervous system disorders. The field encompasses areas such as deep brain stimulation, brain machine interfaces, neurorehabilitation and the development of devices for the sensory nervous system such as the use of auditory implants, retinal implants, and electronic skins.

Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain whose constituents can include brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF).

George K. Michalopoulos is a Greek-American pathologist and academic. He served as Maud L. Menten Professor of Experimental Pathology and Chair of the Department of Pathology at the University of Pittsburgh and UPMC from 1991 to 2023.

Athira Pharma is a late clinical stage American biopharmaceutical company developing small molecules to restore neuronal health and stop the neurodegeneration brought on by diseases such as Alzheimer's disease and Parkinson's disease. The company's lead candidate, ATH-1017, is in human studies for Alzheimer's disease as of 2021.

<span class="mw-page-title-main">Experimental models of Alzheimer's disease</span>

Experimental models of Alzheimer's disease are organism or cellular models used in research to investigate biological questions about Alzheimer's disease as well as develop and test novel therapeutic treatments. Alzheimer's disease is a progressive neurodegenerative disorder associated with aging, which occurs both sporadically or due to familial passed mutations in genes associated with Alzheimer's pathology. Common symptoms associated with Alzheimer's disease include: memory loss, confusion, and mood changes.

References

  1. US 8598118,Harding JW, Wright JW, Benoist CC, Kawas LH, Wayman GA,"Hepatocyte growth factor mimics as therapeutic agents"
  2. Benoist CC, Wright JW, Zhu M, Appleyard SM, Wayman GA, Harding JW (October 2011). "Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs". The Journal of Pharmacology and Experimental Therapeutics. 339 (1): 35–44. doi:10.1124/jpet.111.182220. PMC   3186286 . PMID   21719467.
  3. Uribe PM, Kawas LH, Harding JW, Coffin AB (January 2015). "Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure". Frontiers in Cellular Neuroscience. 9 (3): 3. doi: 10.3389/fncel.2015.00003 . PMC   4309183 . PMID   25674052.
  4. Wright JW, Harding JW (January 2015). "The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease". Journal of Alzheimer's Disease. 45 (4): 985–1000. doi:10.3233/JAD-142814. PMID   25649658.
  5. Siller R, Greenhough S, Naumovska E, Sullivan GJ (May 2015). "Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells". Stem Cell Reports. 4 (5): 939–952. doi:10.1016/j.stemcr.2015.04.001. PMC   4437467 . PMID   25937370.
  6. "32. The Innovators: Designing Medicine's Holy Grail". KOMO News. 27 August 2015. Retrieved 11 October 2015.
  7. "Brain Connections in Alzheimer's Rebuilt with New Peptide". GEN News Highlights. 11 October 2015. Retrieved 11 October 2015.
  8. "Brain-Enhancing 'Smart Drugs' Are Going Commercial". VICE. 17 July 2014. Retrieved 11 October 2015.
  9. "Prospective Alzheimer's drug builds new brain cell connections, improves cognitive function of rats". ScienceDaily. 11 October 2012. Retrieved 11 October 2015.
  10. USpatent 0337024,Allison Coffin, Joseph Harding, Leen Kawas, Phillip Uribe,"Novel Lead Compound for Otoprotection: Targeting HGF Signaling with Dihexa",issued 2015-11-26
  11. "Dihexa" (PDF). Alzheimer's Drug Discovery Foundation. August 13, 2021.
  12. "Fosgonimeton | ALZFORUM". www.alzforum.org. Retrieved 2023-04-20.