(Peptide 5 is the science terminology used for Peptagon™.)
1. Kim Y, Griffin JM, Harris PWR, Chan SHC, Nicholson LFB, Brimble MA, O’Carroll SJ, Green CR. Characterizing the mode of action of extracellular Connexin43 channel blocking mimetic peptides in an in vitro ischemia injury model. Biochim Biophys Acta. 2017; 1861:68-78. Link
This manuscript working with peptide chemists describes the mode of action and site of action of Peptide 5. It shows that Peptide 5 acts on extracellular loop one of the Connexin43 protein, and that even single amino-acid modifications can limit function, indicating a very specific MOA.
2. Mao Y, Tonkin RS, Nguyen T, O’Carroll SJ, Nicholson LFB, Green CR, Moalem-Taylor G, Gorrie CA. Systemic administration of Connexin43 mimetic peptide improves functional recovery following traumatic spinal cord injury in adult rats. J Neurotrauma. 2016; 33:1-13. Link
This work with was with colleagues at the University of New South Wales, Sydney and the University of Technology, Sydney. This closes the circle following up Nexagon® topical delivery published in 2008, Peptide 5 topical delivery (osmotic minipump)published in 2013, and now Peptide 5 systemic delivery (intraperitoneal injection). The team is now analyzing inflammasome levels in these tissues at 6 weeks post-injury with the aim to commence a five arm study in 2017: HCB1019 acute oral (plus control group)and HCB1019 and Peptide 5 starting at 6 weeks (so treating chronic inflammation) (plus control group). It is now well established that human brain traumatic brain injury results in inflammation lasting well over ten years and our spinal cord injury rats still have severe inflammation long after behavioral improvements have leveled indicating intervention in chronic SCI patients may still be beneficial.
3. Willebrords J, Crespo Yanguas S, Maes M, Decrock E, Wang N, Leybaert L, Kwak BR, Green CR, Cogliati B, Vinken M. Connexins and their channels in inflammation. Crit Rev Biochem Mol Biol. 2016 Jul 7:1-27. Link
This a review article with Belgian experts in the connexin channel field. This is the group that coined the term ‘pathological pore’ for the hemichannel.
4. Guo CX, Nor MNM, Danesh-Meyer HV, Vessey K, Fletcher EL, O’Carroll SJ, Acosta ML, Green CR. Connexin43 mimetic peptide improves retinal function and reduces inflammation in a light damaged albino rat model. Investigative Ophthalmology and Visual Science, 2016; 57: 3961-3973. Link
This is a key paper using the bright light-induced retinal injury model (a model ofdry macular degeneration and follows our 2014 manuscript describing gap junction changes in this model. This paper shows reduced inflammation and recovery of eye function with Peptide 5 treated animals. It builds our profile in this field following three Peptide 5 manuscripts (systemic and intravitreal delivery) published on the retinal ischemia-reperfusion model (a model of diabetic retinopathy).
5. Kim Y and Green CR. Assessing Connexin Hemichannel Function. In: Gap Junction and Pannexin Channels, “A Volume in the Methods in Signal Transduction Series”. Ed: Donglin Bai and Juan C. Sáez. CRC Press, Taylor &Francis Group 2016. (No online link available.)
A review chapter describing a new in vitro model of cell ischemia-reperfusion we developed, but also demonstrating Peptide 5 block of ATP release in that model.
Two further reviews have been completed. The first is a major review “Connexins in Cerebrovascular and Retinovascular Disease” (around 1000 references) with colleagues from Belgium, France, Canada, USA and Chile. This will be published in Pharma Reviews (a major pharmacology review journal) with a significant chapter from us on animal models and inflammasome pathway modulation. A review chapter on Connexins and Pannexins in Cerebral Ischemia will appear in a special edition of BBA Biomembranes on gap junction and pannexin channels. Several oral and poster presentations were given at international conferences including an invited presentation at ARVO, Seattle, 2016 (attended by about 300 people and where the inflammasome model and eye data was presented) and the International Symposium on Ocular Pharmaceutics and Therapeutics in Rome, Italy (by a one of our team talking about the inflammasome and bright light model).
Two abstracts have been submitted for the Sonoma Eye conference in February, an important ocular meeting focusing on inflammation pathways in the treatment of ocular disease. These are:
6. Connexin43 (Cx43) the Inflammasome Pathway and treatment of Non Responsive Persistent Corneal Epithelial Defects (PED). Colin R Green Brian Levy Department of Ophthalmology, University of Auckland and New Zealand National Eye Centre, Auckland, New Zealand OcuNexus Therapeutics Inc., San Diego, California
7. Connexin43 (Cx43) and the inflammasome pathway; Effective Therapeutic Targets in Serious Eye Disease. Colin R Green1,2, Brian Levy2, Lola Rotimi1, I lva Rupenthal1, Helen Danesh-Meyer1, Cindy Guo3, Mohd Nasir bin Mat Nor3, Monica Acosta31Department of Ophthalmology, University of Auckland and New Zealand National Eye Centre, Auckland, New Zealand2OcuNexus Therapeutics Inc., San Diego, California3School of Optometry and Vision Sciences, University of Auckland and New Zealand National Eye Centre, Auckland, New Zealand.
Guo CX, Nor MNM, Danesh-Meyer HV, Vessey K, Fletcher EL, O’Carroll SJ, Acosta ML, Green CR. Connexin43 mimetic peptide improves retinal function and reduces inflammation in a light damaged albino rat model. Investigative Ophthalmology and Visual Science, 2016; 57: 3961-3973. Link
Ormonde S, Chou C, Goold L, Petsoglou C, Al-Taie R, Sherwin T, McGhee CNJ and Green CR. Regulation of connexin43 gap junction protein triggers vascular recovery and healing in human ocular persistent epithelial defect wounds. Journal of Membrane Biology. 2012;245: 381 - 388. Link
Danesh-Meyer HV, Kerr NM, Zhang J, Eady EK, O’Carroll SJ, Nicholson LFB, Johnson CS and Green CR. Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia. Brain. 2012;135:506 - 520. (Not available online)
Deva NC, Zhang J, Green CR and Danesh-Meyer HV. Connexin43 modulation inhibits scarring in a rabbit eye glaucoma trabeculectomy model. Inflammation. 2012;35:1276 - 1286. Link
Kim Y, Griffin JM, Harris PW, Chan SH, Nicholson LF, Brimble MA, O'Carroll SJ, Green CR. Characterizing the mode of action of extracellular Connexin43 channel blocking mimetic peptides in an in vitro ischemia injury model. Biochim Biophys Acta. 2016. Link
Danesh-Meyer HV, Zhang J, Acosta ML, Rupenthal ID and Green CR. Connexin43 in retinal injury and disease. Prog Retin Eye Res. 2015; 51:41-68. PMID: 26432657. Review. Link
Kim Y, Davidson JO, Gunn KC, Phillips AR, Green CR and Gunn AJ. Role of hemichannels in CNS inflammation and the inflammasome pathway. Adv Protein Chem Struct Biol. 2016;104:1-37. doi: 10.1016/bs.apcsb.2015.12.001. Epub 2015 Dec 31. Link
Decrock E, De Bock M, Wang N, Bultynck G, Giaume C, Naus CC, Green CR, Leybaert L. Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology? Cell Mol Life Sci. 2015; 72:2823-2851. Link
Willebrords J, Crespo Yanguas S, Maes M, Decrock E, Wang N, Leybaert L, Kwak BR, Green CR, Cogliati B, Vinken M. Connexins and their channels in inflammation. Crit Rev Biochem Mol Biol. 2016 Jul 7:1-27. Link
Mao Y, Tonkin RS, Nguyen T, O’Carroll SJ, Nicholson LFB, Green CR, Moalem-Taylor G, Gorrie CA. Systemic administration of Connexin43 mimetic peptide improves functional recovery following traumatic spinal cord injury in adult rats. J Neurotrauma. 2016 Sep 14. Link
Davidson JO, Green CR, Nicholson LFB, O'Carroll SJ, Fraser M, Bennet L and Gunn AJ. Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Annals of Neurology. 2012;71:121 - 132. Link
Davidson JO, Drury PP, Green CR, Nicholson LF, Bennet L and Gunn AJ. Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep. PLoS One. 2014; 9(5):e96558. Link