cenderitide
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| legal_status = Investigational
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| CAS_number = 507289-11-4
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| DrugBank = 11777
| UNII = 9NKZ9LYZ06
| IUPAC_name = glycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-L-cysteinyl-L-prolyl-L-seryl-L-leucyl-L-arginyl-L-α-aspartyl-L-prolyl-L-arginyl-L-prolyl-L-asparaginyl-L-alanyl-L-prolyl-L-seryl-L-threonyl-L-seryl-L-alanine, cyclic (6→22)-disulfide
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Cenderitide (also known as chimeric natriuretic peptide or CD-NP) is a natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure.{{cite journal | vauthors = McKie PM, Sangaralingham SJ, Burnett JC | title = CD-NP: an innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease | journal = Current Heart Failure Reports | volume = 7 | issue = 3 | pages = 93–9 | date = September 2010 | pmid = 20582736 | doi = 10.1007/s11897-010-0016-6 | s2cid = 23726451 }}{{cite journal | vauthors = Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC | title = Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP | journal = Journal of the American College of Cardiology| volume = 52 | issue = 1 | pages = 60–8 | date = July 2008 | pmid = 18582636 | pmc = 2575424 | doi = 10.1016/j.jacc.2008.02.077 }}{{cite journal | vauthors = Dickey DM, Burnett JC, Potter LR | title = Novel bifunctional natriuretic peptides as potential therapeutics | journal = The Journal of Biological Chemistry | volume = 283 | issue = 50 | pages = 35003–9 | date = December 2008 | pmid = 18940797 | pmc = 3259864 | doi = 10.1074/jbc.M804538200 | doi-access = free }} Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom dendroaspis natriuretic peptide (DNP) with the full C-type natriuretic peptide (CNP) structure. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the natriuretic and diuretic properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.
Molecular problem: fibrosis
When faced with pressure overload, the heart attempts to compensate with a number of structural alterations including hypertrophy of cardiomyocytes and increase of extracellular matrix (ECM) proteins.{{cite journal | vauthors = Bonnin CM, Sparrow MP, Taylor RR | title = Collagen synthesis and content in right ventricular hypertrophy in the dog | journal = The American Journal of Physiology | volume = 241 | issue = 5 | pages = H708–13 | date = November 1981 | pmid = 7304760 | doi = 10.1152/ajpheart.1981.241.5.H708 }}{{cite journal | vauthors = Averill DB, Ferrario CM, Tarazi RC, Sen S, Bajbus R | title = Cardiac performance in rats with renal hypertension | journal = Circulation Research | volume = 38 | issue = 4 | pages = 280–8 | date = April 1976 | pmid = 131007 | doi = 10.1161/01.res.38.4.280 | doi-access = free }} Rapid accumulation of ECM proteins causes excessive fibrosis resulting in decreased myocardial compliance and increased myocardial stiffness.{{cite journal | vauthors = Weber KT | title = Cardiac interstitium in health and disease: the fibrillar collagen network. | journal = Journal of the American College of Cardiology | date = June 1989 | volume = 13 | issue = 7 | pages = 1637–52 | doi = 10.1016/0735-1097(89)90360-4 | pmid = 2656824 | doi-access = free }} The exact mechanisms involved in excessive fibrosis are not fully understood but there is evidence that supports involvement from local growth factors FGF-2, TGF-beta and platelet-derived growth factor.{{cite journal | vauthors = Creemers EE, Pinto YM | title = Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart | journal = Cardiovascular Research | volume = 89 | issue = 2 | pages = 265–72 | date = February 2011 | pmid = 20880837 | doi = 10.1093/cvr/cvq308 | doi-access = free }}{{cite journal | vauthors = Weber KT, Swamynathan SK, Guntaka RV, Sun Y | title = Angiotensin II and extracellular matrix homeostasis | journal = The International Journal of Biochemistry & Cell Biology | volume = 31 | issue = 3–4 | pages = 395–403 | date = 1999 | pmid = 10224666 | doi = 10.1016/s1357-2725(98)00125-3 }}{{cite journal | vauthors = Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA | title = Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 2 | pages = 437–42 | date = January 2005 | pmid = 15625103 | pmc = 544320 | doi = 10.1073/pnas.0408704102 | bibcode = 2005PNAS..102..437S | doi-access = free }} TGF-β1 plays an important role in cardiac remodelling through the stimulation of fibroblast proliferation, ECM deposition and myocyte hypertrophy.{{cite journal | vauthors = Villarreal FJ, Lee AA, Dillmann WH, Giordano FJ | title = Adenovirus-mediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells | journal = Journal of Molecular and Cellular Cardiology | volume = 28 | issue = 4 | pages = 735–42 | date = April 1996 | pmid = 8732501 | doi = 10.1006/jmcc.1996.0068 }}{{cite journal | vauthors = Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B | title = Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts. Regulation of fibrillar collagen mRNAs and expression of early transcription factors | journal = Circulation Research | volume = 69 | issue = 2 | pages = 483–90 | date = August 1991 | pmid = 1860186 | doi = 10.1161/01.res.69.2.483 | doi-access = free }}{{cite journal | vauthors = Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA | title = Myofibroblasts and mechano-regulation of connective tissue remodelling | journal = Nature Reviews. Molecular Cell Biology | volume = 3 | issue = 5 | pages = 349–63 | date = May 2002 | pmid = 11988769 | doi = 10.1038/nrm809 | s2cid = 3353563 }} The increase in TGF-beta 1 expression in a pressure-overloaded heart correlates with the degree of fibrosis, suggesting TGF-beta 1 involvement in the progression from a compensated hypertrophy to failure.{{cite journal | vauthors = Boluyt MO, O'Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, Crow MT, Lakatta EG | title = Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components | journal = Circulation Research | volume = 75 | issue = 1 | pages = 23–32 | date = July 1994 | pmid = 8013079 | doi = 10.1161/01.res.75.1.23 | doi-access = free }}{{cite journal | vauthors = Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J | title = Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms | journal = Circulation | volume = 107 | issue = 7 | pages = 984–91 | date = February 2003 | pmid = 12600911 | doi = 10.1161/01.cir.0000051865.66123.b7 | doi-access = free }} Through an autocrine mechanism, TGF-beta 1 acts on fibroblasts by binding TGF-beta 1 receptors 1 and 2. Upon receptor activation, the receptor-associated transcription factor Smad becomes phosphorylated and associates with Co-Smad.{{cite journal | vauthors = Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massagué J | title = Determinants of specificity in TGF-beta signal transduction | journal = Genes & Development | volume = 12 | issue = 14 | pages = 2144–52 | date = July 1998 | pmid = 9679059 | pmc = 317013 | doi = 10.1101/gad.12.14.2144 }} This newly formed Smad-Co-Smad complex enters the nucleus where it acts as a transcription factor modulating gene expression.
Cardiac remodelling of the ECM is also regulated by the CNP/NPR-B pathway as demonstrated by the improved outcomes in transgenic mice with CNP over-expression subjected to myocardial infarction.{{cite journal | vauthors = Wang Y, de Waard MC, Sterner-Kock A, Stepan H, Schultheiss HP, Duncker DJ, Walther T | title = Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice | journal = European Journal of Heart Failure | volume = 9 | issue = 6–7 | pages = 548–57 | date = 2007 | pmid = 17407830 | doi = 10.1016/j.ejheart.2007.02.006 | doi-access = free }}{{cite journal | vauthors = Langenickel TH, Buttgereit J, Pagel-Langenickel I, Lindner M, Monti J, Beuerlein K, Al-Saadi N, Plehm R, Popova E, Tank J, Dietz R, Willenbrock R, Bader M | title = Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 12 | pages = 4735–40 | date = March 2006 | pmid = 16537417 | pmc = 1450239 | doi = 10.1073/pnas.0510019103 | bibcode = 2006PNAS..103.4735L | doi-access = free }} Binding of CNP to NPR-B catalyzes the synthesis of cGMP, which is responsible for mediating the anti-fibrotic effects of CNP.{{cite book | vauthors = Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM | title = CGMP: Generators, Effectors and Therapeutic Implications | chapter = Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications | series = Handbook of Experimental Pharmacology | issue = 191 | pages = 341–66 | date = 2009 | volume = 191 | pmid = 19089336 | pmc = 4855512 | doi = 10.1007/978-3-540-68964-5_15 | isbn = 978-3-540-68960-7 }}
Fibrotic heart tissue is associated with an increase risk of ventricular dysfunction which can ultimately lead to heart failure.{{cite journal | vauthors = Kenchaiah S, Pfeffer MA | title = Cardiac remodeling in systemic hypertension | journal = The Medical Clinics of North America | volume = 88 | issue = 1 | pages = 115–30 | date = January 2004 | pmid = 14871054 | doi = 10.1016/s0025-7125(03)00168-8 | s2cid = 32530917 }} Thus, anti-fibrotic strategies are a promising approach in the prevention and treatment of heart failure.
Molecular mechanism
As cenderitide interacts with both NRP-A and NRP-B, this drug has antifibrotic potential. Binding of cenderitide to NRP-B elicits an antifibrotic response by catalyzing formation of cGMP similar to the response seen with endogenous CNP. Additionally, in vitro study of human fibroblasts demonstrates that cenderitide reduces TGF-beta 1 induced collagen production.{{cite journal | vauthors = Ichiki T, Huntley BK, Sangaralingham SJ, Chen HH, Burnett Jr JC | title = A novel designer natriuretic peptide CD-NP suppresses TGF-beta 1 induced collagen type I production in human cardiac fibroblasts. | journal = Journal of Cardiac Failure | date = 2009 | volume = 15 | issue = 6 supplement | pages = S34 | doi = 10.1016/j.cardfail.2009.06.318 }} These two proposed mechanisms illustrate therapeutic potential for the reduction of fibrotic remodelling in the hypertensive heart. Through combined effects of CNP and DNP, cenderitide treatment results in a reduction in stress on the heart (through natriuresis/diuresis) and inhibition of pro-fibrotic, remodeling pathways.