Stanger K, Steffek M, Zhou L, Pozniak CD, Quan C, Franke Y, Tom J, Tam C, Elliott JM, Lewcock JW, Zhang Y, Murray J, Hannoush RN.
Allosteric peptides bind a caspase zymogen and mediate caspase tetramerization.
Nat Chem Biol. 2012 Jul;8(7):655-60.
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A variety of caspases have been implicated over the last 15 years in regulating the extensive neuron degeneration that occurs in Alzheimer's disease. Originally, most investigators focused on the effector caspase, caspase-3, whose activity in many experimental systems was found to be a critical trigger for neuron apoptosis. Since neuron death is now widely recognized as a late event in the course of Alzheimer's disease pathogenesis, occurring well after synapse loss and neuronal cytoskeletal changes have occurred, the potential therapeutic utility of developing inhibitors of effector (executioner) caspases would at first glance appear limited. However, a series of studies performed over the last five to 10 years have consistently drawn attention to a potentially unique role of a second effector caspase, caspase-6, in cell death-independent neurodegeneration. Caspase-6 exists at baseline in neurons as an inactive precursor (zymogen) that is cleaved by initiator caspases into large and small subunits which together form the active caspase-6 enzyme. Unlike caspase-3, which triggers neuron death and destruction of the neuronal cell body, activated caspase-6 has been implicated in degradation of synapses and neuronal processes. Elevated levels of activated caspase-6 have been found in Alzheimer's disease brain and in the brains of patients with mild cognitive impairment prior to extensive neuron loss, suggesting that caspase-6 may play an important role in regulating the earliest pathological events in Alzheimer's disease progression. Thus, inhibition of caspase-6 activity may represent a new and important therapeutic target for attenuating the neuropathological changes observed in Alzheimer's disease, and potentially delaying or preventing neurocognitive decline.
The article by Stanger et al. is potentially an important first step in developing just such an inhibitor. To date, there has been very limited success in developing specific inhibitors of individual caspases, since the caspases represent a relatively large family with extensive sequence and structural homology. Broad spectrum caspase inhibitors that target the active site of multiple caspases have not yet been proven therapeutically useful due to a variety of side effects. Given the pleiotropic effects of caspases and the important homeostatic function of regulated cell death in a variety of organs, it is perhaps not surprising that these broad caspase inhibitors have not yet proven effective in treating human chronic diseases.
In the current article, Stanger et al. have taken a different approach to identifying an effective and specific caspase-6 inhibitor. Rather than targeting the active site of the "processed" active caspase-6 enzyme, they used phage display to discover peptides that bind to the caspase-6 zymogen and screened such compounds for their effects on caspase-6 enzymatic activity. They report the identification of pep419 as a selective allosteric inhibitor of caspase-6 function with minimal inhibitory activity on other caspases. Pep419 was found to selectively inhibit the degradation of a caspase-6 substrate in a cell culture model of neuronal apoptosis, and did not inhibit the degradation of caspase-3 or caspase-7 substrates in the same experimental system. Although it is unclear if pep419 can selectively inhibit caspase-6 activity in vivo, the article describes several important conceptual advances. First, selective caspase inhibitors can be developed by targeting caspase zymogens rather than the active enzymes themselves; second, the molecular mechanism by which pep419 inhibits caspase-6 activity is distinct from previously developed small molecule caspase inhibitors; and third, phage display screening against caspase zymogens may lead to the development of small molecule allosteric ligands that selectively inhibit the activity of specific caspases in vivo. Further research and drug development is essential to move these findings into clinical settings, but if effective and safe caspase-6 specific inhibitors can be developed, they would hold significant promise as Alzheimer's disease-altering agents, since increased caspase-6 activity may play an early and relatively selective role in Alzheimer's disease-related neurodegeneration prior to irreversible neuron loss.