The potential for caspases in drug discovery

Abstract

Caspases are a family of proteases that are involved in the execution of apoptosis and the inflammatory response. A plethora of diseases occur as a result of the dysregulation of apoptosis and inflammation, and caspases have been targeted as a therapeutic strategy to halt the progression of such diseases. Hundreds of peptide and peptidomimetic inhibitors have been designed and tested, but only a few have advanced to clinical trials because of poor drug-like properties and pharmacological constraints. Although much effort has been focused on inhibiting caspases, there are many diseases that result from a decrease in apoptosis, thus activating procaspases could also be a viable therapeutic strategy. To this end, recent efforts have focused on the design of procaspase-3 activators. This review highlights the current progress in the rational design of both specific and pan-caspase inhibitors, as well as procaspase-3 activators.

Figure 1. The structure of the WEHD tetrapeptide in the active site of capsase-1

The peptide inhibitor Ac-Trp-Glu-His-Asp-CHO (WEHD; P4 to P1) forms numerous interactions with the active site of caspase-1, including hydrogen bonds (dotted lines) and hydrophobic interactions (triple dashes). This figure was adapted from the crystal structure of inhibitor bound caspase-1 (Protein Data Bank identifier: 1IBC).

Figure 2. Structures of promising compounds for caspase inhibition

Promising lead compounds for caspase inhibition include pralnacasan and VX-765, reversible caspase-1 inhibitors; emricasan, an irreversible pan-caspase inhibitor; and NCX-1000, a nitric oxide-donor caspase inhibitor.

Figure 3. Structures of the active and allosteric sites of caspases

(A) The location of the active site of one monomer (black circle) and an allosteric site in the dimer interface (black rectangle) are depicted (Protein Data Bank identifier: 2J30). (B) and (C) The presence of the allosteric inhibitors FICA (Protein Data Bank identifier: 1SHL) and DICA (Protein Data Bank identifier: 1SHJ), respectively, in the dimer interface both result in the same movement of Tyr²²³ (situated in the dimer interface) that prevents the insertion of Arg¹⁸⁷ (situated on the active site loop L2), resulting in a disordered and non-functional active site. In the dimer interface of procaspase-7 (blue protein structure), the intact intersubunit linker causes Tyr²²³ to point away from the dimer interface compared with the same residue in active caspase-7 (green protein structure).

Figure 4. The structure of executioner procaspase conformations

The executioner procaspases exist in a strongly favored inactive conformation (A) and an active conformation (B). Interactions between the intersubunit linker (IL; red line) and the dimer interface prevent active site formation. Removal of these loops (Ls) from the dimer interface may be the switch that allows the formation of the fully functional active site. Structures are homology models based on procaspase-7 (A) and caspase-3 (B), as described in reference [53].

Figure 5. The structures of example small molecules that lead to procaspase-3 activation