Proteases (medical and related uses)

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See also article: Protease, for structure and properties of proteolytic enzymes

Proteases (also sometimes referred to as proteolytic enzymes or peptidases) are in use, or have been proposed or tried, for a number of purposes related to medicine or surgery. Some preparations involving protease have undergone successful clinical trials and have regulatory authorization;[1] and some further ones have shown apparently useful effects in experimental medical studies.[2] Proteases have also been used by proponents of alternative therapies, or identified in materials of traditional or folk medicine.[3] A serine protease of human origin, activated protein C, was produced in recombinant form and marketed as Drotrecogin alfa (also known as Xigris (TM)) and licensed for intensive-care treatment of severe sepsis. It was voluntarily withdrawn by the manufacturer in 2011 after being shown to be ineffective.[4][5]

Some of these uses rely directly on the proteolytic activity: others rely on observations of anti-inflammatory activity.

Medical and surgical applications based on proteolytic effect[edit]

Treatment of blood clots in ischemic stroke[edit]

Tissue plasminogen activator (TPA) is a serine protease occurring in animals including humans. Human-identical TPA (produced industrially by genetically recombinant microorganisms) has an established medical use in the treatment of ischemic stroke: by its proteolytic activity it enables the action of another enzyme (plasmin), which breaks down the protein (fibrin) of blood clots.

Wound debridement[edit]

Debridement involves the removal of dead or damaged tissue from wounds in order to assist healing. Much of the debris to be removed is proteinaceous, and proteolytic enzymes have been applied to this purpose.

Papain is a protease obtained from the latex of the fruit of the papaya tree. It has been used (without regulation) for wound debridement for many years, but in the USA in 2008 it was brought under regulation by the U.S. Food and Drug Administration and removed from sale for this purpose, following reports of adverse effects. On the other hand, recent research has been exploring new ways of administering papain for wound debridement.[6]

Papain as well as other proteases, including bromelain, collagenase, trypsin and thermolysin, have also been tried or used according to other reports on the use of proteases for debridement of wounds and burns without damaging healthy tissue.[7]

Maggot therapy for wound debridement is a traditional therapy which was in recent years approved by the FDA.[8] It has been identified that the maggots produce proteolytic enzymes which take part in the debridement process.[9]

Applications of proteases auxiliary to antibiotic therapy[edit]

Some pathogenic bacteria produce biofilms or exudates containing protein, which in some degree help the bacteria adhere to host tissue, or in some degree physically shield the bacteria or hinder the penetration of substances such as antibiotics administered with the intent that they contact the bacteria. Accordingly, proteolytic enzymes have been tried in conjunction with antibiotics. Thus, it has been reported that Serratia E-15 protease (also known as serratiopeptidase)[10] was effective for eradicating infection caused by biofilm-forming bacteria in an experimental animal model (which involved carrying out experimental limb surgery on rats, at the same time experimentally introducing Staphylococcus infection). The authors considered that "The antibiofilm property of the enzyme may enhance antibiotic efficacy in the treatment of staphylococcal infections."[11]

The same enzyme, when used concomitantly with an antibiotic, was also reported to increase antibiotic concentration at a target site.[12]

Applications of protease based on anti-inflammatory activity[edit]

Bromelain is a protease usually obtained from pineapple stem tissue, which has been medically used for its anti-inflammatory effects (see Bromelain - medical uses).

Serratia E-15 protease (also known as serratiopeptidase or 'serrapeptidase')[10] is another protease that has been proposed as an anti-inflammatory agent.[13] Anti-inflammatory effects of this protease have been reported again more recently,[14] and the material has come into some use in alternative or complementary medicine. On the other hand, it does not appear that there are positive clinical trial results for this material of a kind that would be needed to gain regulatory approval for controlled pharmaceutical uses.[15]

References[edit]

  1. ^ See Tissue plasminogen activator and Maggot therapy.
  2. ^ Examples are reported by M. Mecikoglu et al., "The Effect of Proteolytic Enzyme Serratiopeptidase in the Treatment of Experimental Implant-Related Infection", The Journal of Bone and Joint Surgery (American) vol.88 (2006), pp.1208-1214; see also bromelain and papain.
  3. ^ Examples include Serratia E-15 protease (Serratiopeptidase) (see also separate references in this list); Wobenzym (a mixture of bromelain and papain); and Maggot therapy.
  4. ^ "Xigris (drotrecogin alfa (activated)) to be withdrawn due to lack of efficacy". Press release. London, UK: European Medicines Agency. 25 October 2011. Archived from the original on 26 October 2011. Retrieved 26 October 2011. 
  5. ^ http://www.businessweek.com/news/2011-10-25/lilly-pulls-xigris-off-markets-after-sepsis-drug-fails-study.html
  6. ^ Yaakobi, Tali; Roth, Dalit; Chen, Yoram; Freeman, Amihay (July 2007). "Streaming of Proteolytic Enzyme Solutions for Wound Debridement: A Feasibility Study". Wounds 19 (7). 
  7. ^ Klasen HJ (May 2000). "A review on the nonoperative removal of necrotic tissue from burn wounds". Burns 26 (3): 207–22. doi:10.1016/S0305-4179(99)00117-5. PMID 10741585. 
  8. ^ See article Maggot therapy -- Regulation and references cited therein.
  9. ^ Reames MK, Christensen C, Luce EA (October 1988). "The use of maggots in wound debridement". Annals of Plastic Surgery 21 (4): 388–91. doi:10.1097/00000637-198810000-00017. PMID 3232928. 
  10. ^ a b Serratia E-15 protease, otherwise known as serratiopeptidase, first prepared in the late 1960s, is obtained from Serratia sp. E-15, which was isolated from silkworm Bombyx mori L. (intestine), and deposited with the American Type Culture Collection as strain ATCC 21074 (enter 21074 on ATCC/LGC search page for information). Within the ATCC the micro-organism is alternatively named Serratia marcescens Bizio. The preparation and some uses of the protease are described in US Patent 3,792,160, issued 12 Feb 1974: M Isono, et al., for Method of treating inflammation and composition therefor. The material is also described in K K Miyata, K Maejima, K Tomoda, & M Isono, Serratia protease. Part I. Purification and general properties of the enzyme., Agricultural and Biological Chemistry, (1970) v.34, pp 310-318.
  11. ^ Mecikoglu M, Saygi B, Yildirim Y, Karadag-Saygi E, Ramadan SS, Esemenli T (June 2006). "The effect of proteolytic enzyme serratiopeptidase in the treatment of experimental implant-related infection". The Journal of Bone and Joint Surgery 88 (6): 1208–14. doi:10.2106/JBJS.E.00007. PMID 16757752. 
  12. ^ Okumura H, Watanabe R, Kotoura Y, Nakane Y, Tangiku O (March 1977). "[Effects of a proteolytic-enzyme preparation used concomitantly with an antibiotic in osteoarticular infections (author's transl)]". The Japanese Journal of Antibiotics (in Japanese) 30 (3): 223–7. PMID 853579. 
  13. ^ See US Patent 3,792,160, issued 12 Feb 1974: M Isono, et al., for Method of treating inflammation and composition therefor. The material is also described in K K Miyata, K Maejima, K Tomoda, & M Isono, Serratia protease. Part I. Purification and general properties of the enzyme., Agricultural and Biological Chemistry, (1970) v.34, pp 310-318.
  14. ^ P M Esch, H Gerngross, A Fabian, Reduction of postoperative swelling. Objective measurement of swelling of the upper ankle joint in treatment with serrapeptase -- a prospective study, Fortschritte der Medizin, 02/1989; vol 107(4):pp 67-8, 71-2; (ISSN 0015-8178).
  15. ^ "Serratiopeptidase - finding the evidence", an article available at Bandolier (online journal).