Emerging principles in protease-based drug discovery

Abstract

Proteases have an important role in many signalling pathways, and represent potential drug targets for diseases ranging from cardiovascular disorders to cancer, as well as for combating many parasites and viruses. Although inhibitors of well-established protease targets such as angiotensin-converting enzyme and HIV protease have shown substantial therapeutic success, developing drugs for new protease targets has proved challenging in recent years. This in part could be due to issues such as the difficulty of achieving selectivity when targeting protease active sites. This Perspective discusses the general principles in protease-based drug discovery, highlighting the lessons learned and the emerging strategies, such as targeting allosteric sites, which could help harness the therapeutic potential of new protease targets.Proteins are among the most stable biological polymers. Peptide bonds can withstand hours in boiling concentrated acid, yet they last no more than microseconds in the presence of a specific protease. The study of proteolysis goes back at least to the nineteenth century with the description of pepsin by Schwann in 1836 and of trypsin by Corvisart in 1856. Since then, proteases have been identified in almost every organism, have been discovered to play a part in most biological pathways 1 and have been implicated in almost every disease.Historically, much of the focus has been on the role of proteases in coagulopathies, inflammation, infectious diseases, cancer and degenerative diseases, and some protease inhibitors have been developed into highly successful drugs. For example, inhibitors of the human protease angiotensin-converting enzyme (ACE), such as captopril, have been used in the treatment of cardiovascular disorders, primarily hypertension and congestive heart failure, for several decades 2 . In addition, inhibitors of the HIV protease, such as ritonavir, atazananvir and tipranavir (Aptivus; Pfizer/Boehringer Ingelheim), have had a key role in transforming the treatment of HIV infection since their introduction in the mid-1990s 3 (see TABLE 1 Published in final edited form as:Nat Rev Drug Discov. 2010 September ; 9(9): 690-701. doi:10.1038/nrd3053. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sales of US$1 billion, which is anticipated to rise to $3.5 billion by 2014 (REF. 4 ), whereas antihypertensive drugs that act on the proteases in the renin-angiotensin system currently have over $6 billion global sales 1 . Indeed, at present, we estimate that 5-10% of all pharmaceutical targets being pursued for drug development are proteases.The general strategy for therapeutically targeting proteases is to identify a specific inhibitor -generally a small molecule -that blocks the active site. As discussed below, discovery efforts for new inhibitors have typically been based on the structure of known protease substrates, presenting a substantial challenge for the development of peptidomimetic compounds that have the pharmacokinetic characteristics needed to be sui...

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