Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1999-07-15
2000-03-14
Slobodyansky, Elizabeth
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
514 12, 530324, A61K 3900, A61K 3857, C07K 1481
Patent
active
060369582
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to an inhibitor of thrombin isolated and purified from tsetse flies.
BACKGROUND OF THE INVENTION
Hematophagous arthropods have evolved a variety of strategies to facilitate the taking of a blood meal from their vertebrate hosts. Central to the success of these bloodfeeders is their ability to effectively interfere with host coagulation, thereby allowing for rapid and uninterrupted ingestion of blood from lacerated vessels in the epidermis. To this end, many bloodfeeding species, including ticks.sup.1,2 sandflies.sup.3, redivided bugs.sup.4,5 blackflies.sup.6 and mosquitoes.sup.7,8, produce potent antihemostatic substances, which include anticoagulants, anti-platelet agents, and vasodilators.
Tsetse flies are an important vector of African trypanosomiasis, or sleeping sickness, a devastating disease of humans caused by infection with the hemoflagellate protozoa Trypanosoma brucei gambiense and T.b. rhodesiense.sup.9. These salivarian parasites are injected into the skin of their host while the tsetse feeds on blood. Previously, the saliva of the tsetse fly Glossina morsitans morsitans has been shown to contain a potent inhibitor of mammalian coagulation.sup.10. While initially reported to function as an "antikinase".sup.11, it was subsequently shown that the tsetse anticoagulant was most likely an inhibitor of thrombin.sup.10, a serine protease in the mammalian coagulation cascade that cleaves fibrinogen to fibrin, leading to clot formation at sites of vessel damage. In addition to its anticoagulant effect, tsetse saliva also interferes with human platelet aggregation. Some of this activity has been attributed to a low molecular weight fraction of G.m. morsitans saliva (MW 11,000-13,000 Da), which acts as a potent inhibitor of thrombin induced platelet aggregation.sup.12.
Tsetse are generally considered one of the single greatest factors affecting the course of economic and social development in Africa. For centuries, tsetse flies have had a great impact on human health, both as efficient vectors of try-panosomes that cause extreme human suffering in African sleeping sickness, and as vectors of trypanosomes that kill non-native animals, preventing the development of animal domestication. More than 30 species of wild animals native to Africa harbor trypanosomes that are pathogenic when transmitted to domestic animals. The disease associated with any of these infections is called nagana. Nagana continues to have a major impact in preventing the development of commercial domestic animal production over about one-third of the African continent. The scarcity of domestic animals results in a severe lack of animal protein for use as human food, a lack of draught animals for use in crop production, and the absence of manure suitable for use as fertilizer. At present, about 40 million cattle and millions of sheep, goats, horses, mules, pigs, and camels are risk of infection in Africa. Unlike African sleeping sickness, in which human disease does not occur over the entire distribution of tsetse vectors, in nagana, domestic animal disease whereever tsetse are found, in additon to other areas where infection can be maintained by mechanical transmission by biting flies other than tsetse.
It would be desirable to provide a new anticoagulant having advantageous properties, and to control the significant morbidity and mortality caused by African sleeping sickness and nagana.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a new anticoagulant useful for medical and veterinary purposes.
It is another object of the invention to provide a potent and specific thrombin inhibitor isolated and purified from tsetse flies.
It is a further and more specific object of the invention to provide a thrombin inhibitor that can be used as an antithrombotic agent and a therapeutic agent for the treatment of numerous vascular disorders such as restenosis following percuntaeous angioplasty, and as a vaccine for trypanosomiasis for human beings and animals.
These and other objec
REFERENCES:
Cupp et al. (1998) Blood-feeding strategy of Haematobia irritans (Diptera: Muscidae), Journal of Medical Entomology, vol. 35(4), pp. 591-595.
Ribeiro et al. (1994) Salivary vasodilators of Aedes triseriatus and Anopheles gambiae (Diptera: Culicidae). Journal of Medical Entomology, vol. 31(5), pp. 747-753.
Cappello, M., et al., "Isolation and Characterization of Tsetse Thrombin Inhibitor" Am. J. Trop. Med. Hyg. 54: 475-480 (1996).
Cappello, M., et al., Tsetse Trhombin Inhibitor: Bloodmeal-Induced Expression Proc. Nat. Acad. Sci. USA 95: 14290-14295 (1998).
Mant, M.J. & Parker, K.R., "Two Platelet Aggregation Inhibitors in Tsetse Saliva" Brit. J. Haematology 48: 601-608 (1981).
Parker, K.R., & Mant, M.J., "Effects of Tsetse Salivary Gland Homogenates on Coagulation" Thrombos. Haemostas. 42:743-750 (1979).
Aksoy Serap
Cappello Michael
Krinsky Mary M.
Slobodyansky Elizabeth
Yale University
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