The Normal Coagulation Mechanism

Bennett, Bruce; Ratnoff, Oscar D.

doi:10.1016/s0025-7125(16)32425-7

Cited by 21 publications

(7 citation statements)

References 69 publications

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“…The concept of proteases acting in proteolytic cascades was developed by Davie, Ratnoff and MacFarland during their pioneering work on blood coagulation around 40 years ago7-10. Since that time, several other proteolytic cascades have been postulated, for example, in fibrinolysis, complement fixation, apoptosis and gastrulation (BOX 1).…”

Section: Proteolytic Pathwaysmentioning

confidence: 99%

Emerging principles in protease-based drug discovery

Drąg

Salvesen

2010

Nat Rev Drug Discov

507

458

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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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Section: Proteolytic Pathwaysmentioning

confidence: 99%

Emerging principles in protease-based drug discovery

Drąg

Salvesen

2010

Nat Rev Drug Discov

507

458

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“…Through specific protein-protein interactions, several SP zymogens can form a cascade pathway in which one protease activates the zymogen of another to mediate a rapid, local reaction. The blood clotting cascade in human plasma, the prophenoloxidase activating system (proPO system) in arthropods and the clotting cascade in Limulus haemolymph are classical examples of such SP system [4][5][6]. Serine Proteinase is an important enzyme in the needed for the induction of prophenoloxidase, tissue damage and microbial infection, respectively and signal transduction cascade [7].…”

Section: Introductionmentioning

confidence: 99%

In silico Homology Modeling of Prophenoloxidase activating factor Serine Proteinase Gene from the Haemocytes of Fenneropenaeus indicus

Vaseeharan¹

2011

JPB

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“…Many of the biological processes with the participation of SPs and SPHs were in essence proteolytic cascades [7,16], such as the blood clotting cascade in human plasma and Limulus polyphemus haemocytes [17][18][19], the prophenoloxidase activating system (proPO system) in arthropods, and the dorsoventral patterning cascade in D. melanogaster. In these cascades, one SP activates the inactive precursor of the next SP to mediate a rapid local reaction.…”

Section: Introductionmentioning

confidence: 99%