title: Exploiting differences in caspase-2 and -3 S₂ subsites for selectivity: structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors.
abstract: Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P(2) residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S(2) pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ∼200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.
authors: CHDI Management, Inc., 6080 Center Drive Suite 100, Los Angeles, CA 90045, USA. michel.maillard@chdifoundation.org
authors: Michel C
authors: MC
authors: Maillard
authors: Frederick A
authors: FA
authors: Brookfield
authors: Stephen M
authors: SM
authors: Courtney
authors: Florence M
authors: FM
authors: Eustache
authors: Mark J
authors: MJ
authors: Gemkow
authors: Rebecca K
authors: RK
authors: Handel
authors: Laura C
authors: LC
authors: Johnson
authors: Peter D
authors: PD
authors: Johnson
authors: Mark A
authors: MA
authors: Kerry
authors: Florian
authors: F
authors: Krieger
authors: Mirco
authors: M
authors: Meniconi
authors: Ignacio
authors: I
authors: Muñoz-Sanjuán
authors: Jordan J
authors: JJ
authors: Palfrey
authors: Hyunsun
authors: H
authors: Park
authors: Sabine
authors: S
authors: Schaertl
authors: Malcolm G
authors: MG
authors: Taylor
authors: Derek
authors: D
authors: Weddell
authors: Celia
authors: C
authors: Dominguez
mesh_terms: D001665:Binding Sites; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D020134:Catalytic Domain; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010880:Piperidines / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D013379:Substrate Specificity
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007546:Isoquinolines; D010880:Piperidines; C032727:piperidine; D011392:Proline; D053143:Caspase 2; D053148:Caspase 3; C039109:isoquinoline