2. Academic Validation
  3. Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

  • Amino Acids. 2019 Jan;51(1):7-16. doi: 10.1007/s00726-018-2601-z.
Jiedong Qiu 1,  Sibylle J Hauske 1,  Shiqi Zhang 1,  Angelica Rodriguez-Niño 1,  Thomas Albrecht 1,  Diego O Pastene 1,  Jacob van den Born 2,  Harry van Goor 3,  Sven Ruf 4,  Markus Kohlmann 4,  Michael Teufel 4 5,  Bernhard K Krämer 1 6,  Hans-Peter Hammes 1 6,  Verena Peters 7,  Benito A Yard 1 6,  Aimo Kannt 8 9
Affiliations

Affiliations

  • 1 5th Medical Department, Universitätsklinikum Mannheim, Mannheim, Germany.
  • 2 Department of Nephrology, University Medical Centre Groningen, Groningen, Netherlands.
  • 3 Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, Netherlands.
  • 4 Sanofi Research and Development, Frankfurt am Main, Germany.
  • 5 Translational Medicine Oncology, Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA.
  • 6 European Center for Angioscience, Mannheim, Germany.
  • 7 Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
  • 8 Sanofi Research and Development, Frankfurt am Main, Germany. Aimo.Kannt@Sanofi.com.
  • 9 Institute of Experimental Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Aimo.Kannt@Sanofi.com.
PMID: 29922921 DOI: 10.1007/s00726-018-2601-z
Abstract

Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a Ki of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.

Keywords

Aminoacyl-histidine dipeptidase; Carnosine; Diabetic nephropathies; Drug discovery.

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