Cenderitide Explained

Legal Status:Investigational
Cas Number:507289-11-4
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

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.[1] [2] [3] 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.[2] 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.[1] [3]

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.[4] [5] Rapid accumulation of ECM proteins causes excessive fibrosis resulting in decreased myocardial compliance and increased myocardial stiffness.[5] [6] 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.[7] [8] [9] TGF-β1 plays an important role in cardiac remodelling through the stimulation of fibroblast proliferation, ECM deposition and myocyte hypertrophy.[10] [11] [12] 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.[13] [14] 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.[15] This newly formed Smad-Co-Smad complex enters the nucleus where it acts as a transcription factor modulating gene expression.[15] 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.[16] [17] Binding of CNP to NPR-B catalyzes the synthesis of cGMP, which is responsible for mediating the anti-fibrotic effects of CNP.[18] Fibrotic heart tissue is associated with an increase risk of ventricular dysfunction which can ultimately lead to heart failure.[5] [19] 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.[1] 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.[1] [20] 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.[1]

Notes and References

  1. McKie PM, Sangaralingham SJ, Burnett JC . CD-NP: an innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease . Current Heart Failure Reports . 7 . 3 . 93–9 . September 2010 . 20582736 . 10.1007/s11897-010-0016-6 . 23726451 .
  2. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC . Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP . Journal of the American College of Cardiology. 52 . 1 . 60–8 . July 2008 . 18582636 . 2575424 . 10.1016/j.jacc.2008.02.077 .
  3. Dickey DM, Burnett JC, Potter LR . Novel bifunctional natriuretic peptides as potential therapeutics . The Journal of Biological Chemistry . 283 . 50 . 35003–9 . December 2008 . 18940797 . 3259864 . 10.1074/jbc.M804538200 . free .
  4. Bonnin CM, Sparrow MP, Taylor RR . Collagen synthesis and content in right ventricular hypertrophy in the dog . The American Journal of Physiology . 241 . 5 . H708–13 . November 1981 . 7304760 . 10.1152/ajpheart.1981.241.5.H708 .
  5. Averill DB, Ferrario CM, Tarazi RC, Sen S, Bajbus R . Cardiac performance in rats with renal hypertension . Circulation Research . 38 . 4 . 280–8 . April 1976 . 131007 . 10.1161/01.res.38.4.280 . free .
  6. Weber KT . Cardiac interstitium in health and disease: the fibrillar collagen network. . Journal of the American College of Cardiology . June 1989 . 13 . 7 . 1637–52 . 10.1016/0735-1097(89)90360-4 . 2656824 . free .
  7. Creemers EE, Pinto YM . Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart . Cardiovascular Research . 89 . 2 . 265–72 . February 2011 . 20880837 . 10.1093/cvr/cvq308 . free .
  8. Weber KT, Swamynathan SK, Guntaka RV, Sun Y . Angiotensin II and extracellular matrix homeostasis . The International Journal of Biochemistry & Cell Biology . 31 . 3–4 . 395–403 . 1999 . 10224666 . 10.1016/s1357-2725(98)00125-3 .
  9. Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA . Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase . Proceedings of the National Academy of Sciences of the United States of America . 102 . 2 . 437–42 . January 2005 . 15625103 . 544320 . 10.1073/pnas.0408704102 . 2005PNAS..102..437S . free .
  10. Villarreal FJ, Lee AA, Dillmann WH, Giordano FJ . Adenovirus-mediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells . Journal of Molecular and Cellular Cardiology . 28 . 4 . 735–42 . April 1996 . 8732501 . 10.1006/jmcc.1996.0068 .
  11. Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B . 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 . Circulation Research . 69 . 2 . 483–90 . August 1991 . 1860186 . 10.1161/01.res.69.2.483 . free .
  12. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA . Myofibroblasts and mechano-regulation of connective tissue remodelling . Nature Reviews. Molecular Cell Biology . 3 . 5 . 349–63 . May 2002 . 11988769 . 10.1038/nrm809 . 3353563 .
  13. Boluyt MO, O'Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, Crow MT, Lakatta EG . Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components . Circulation Research . 75 . 1 . 23–32 . July 1994 . 8013079 . 10.1161/01.res.75.1.23 . free .
  14. Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J . Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms . Circulation . 107 . 7 . 984–91 . February 2003 . 12600911 . 10.1161/01.cir.0000051865.66123.b7 . free .
  15. Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massagué J . Determinants of specificity in TGF-beta signal transduction . Genes & Development . 12 . 14 . 2144–52 . July 1998 . 9679059 . 317013 . 10.1101/gad.12.14.2144 .
  16. Wang Y, de Waard MC, Sterner-Kock A, Stepan H, Schultheiss HP, Duncker DJ, Walther T . Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice . European Journal of Heart Failure . 9 . 6–7 . 548–57 . 2007 . 17407830 . 10.1016/j.ejheart.2007.02.006 . free .
  17. 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 . Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B . Proceedings of the National Academy of Sciences of the United States of America . 103 . 12 . 4735–40 . March 2006 . 16537417 . 1450239 . 10.1073/pnas.0510019103 . 2006PNAS..103.4735L . free .
  18. Book: Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM . CGMP: Generators, Effectors and Therapeutic Implications . Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications . Handbook of Experimental Pharmacology . 191 . 341–66 . 2009 . 191 . 19089336 . 4855512 . 10.1007/978-3-540-68964-5_15 . 978-3-540-68960-7 .
  19. Kenchaiah S, Pfeffer MA . Cardiac remodeling in systemic hypertension . The Medical Clinics of North America . 88 . 1 . 115–30 . January 2004 . 14871054 . 10.1016/s0025-7125(03)00168-8 . 32530917 .
  20. Ichiki T, Huntley BK, Sangaralingham SJ, Chen HH, Burnett Jr JC . A novel designer natriuretic peptide CD-NP suppresses TGF-beta 1 induced collagen type I production in human cardiac fibroblasts. . Journal of Cardiac Failure . 2009 . 15 . 6 supplement . S34 . 10.1016/j.cardfail.2009.06.318 .

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