Dihexa (PNB-0408)

Dihexa (PNB-0408) (N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide) is an oral active, blood-brain barrier-permeable angiotensin IV analogue. Dihexa (PNB-0408) is a synthetically derived Angiotensin IV analog that is blood-brain barrier permeable, stable, and orally bioavailable^[1].

Under Dihexa (PNB-0408) stimulation, the hepatocyte growth factor (HGF)/c-Met receptor system can induce dendritic dendrites and synaptogenesis^[2]. The hepatoblasts were differentiated into HLCs by Dihexa and dexamethasone^[3]. Dihexa(PNB-0408)( 0.1 µM) combining Vitamin C, and Forskolin (VDF) could substitute growth factors to induce hepatic specification^[4]. Dihexa (PNB-0408) at both concentrations(10-10 M and 10-12 M; 30 minutes; room temperature) markedly augmented the capacity of HGF to activate c-Met^[5].

Dihexa (PNB-0408) (1.44/2.88 mg/kg ;i.g.; 3 months) restored AngIV decline in APP/PS1 mice, saved the cognitive function of mice, improved neuronal loss in mice and reduced neuroinflammation and inhibited glial activation in the mouse brain^[6]. Dihexa (PNB-0408)(10-6M-10-13M;30 min) protects lateral line hair cells from aminoglycoside ototoxicity. Dihexa does not alter the entry of aminoglycosides into hair cells but rather attenuates cell death through an HGF-dependent signaling mechanism ^[7]. Dihexa (PNB-0408) (2-4mg/kg;b.wt.;16 weeks) is promising candidates for adjunct therapies to promote limb functional recovery after surgical nerve repair, and have implications in peripheral nerve injury and limb transplantation^[8].

References:
[1]. McCoy AT, Benoist CC, et,al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. doi: 10.1124/jpet.112.199497. Epub 2012 Oct 10. PMID: 23055539; PMCID: PMC3533412.
[2]. Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. doi: 10.3233/JAD-142814. PMID: 25649658.
[3]. Mathapati S, Siller R, et,al. Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol. 2016 Aug 17;38:1G.6.1-1G.6.18. doi: 10.1002/cpsc.13. PMID: 27532814.
[4]. Pan T, Wang N, et,al. Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy. Stem Cell Res Ther. 2022 Apr 11;13(1):159. doi: 10.1186/s13287-022-02831-1. PMID: 35410439; PMCID: PMC8996222.
[5]. Benoist CC, Kawas LH, et,al.The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. doi: 10.1124/jpet.114.218735. Epub 2014 Sep 3. PMID: 25187433; PMCID: PMC4201273.
[6]. Sun X, Deng Y,et,al. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci. 2021 Nov 11;11(11):1487. doi: 10.3390/brainsci11111487. PMID: 34827486; PMCID: PMC8615599.
[7]. Uribe PM, Kawas LH, et,al. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Front Cell Neurosci. 2015 Jan 28;9:3. doi: 10.3389/fncel.2015.00003. PMID: 25674052; PMCID: PMC4309183.
[8]: Weiss JB, Phillips CJ, et,al.Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies. Ann Med Surg (Lond). 2021 Oct 8;71:102917. doi: 10.1016/j.amsu.2021.102917. PMID: 34703584; PMCID: PMC8524106.