Patent Application: US-51676107-A

Abstract:
a method for the therapeutic treatment of psoriasis by the administration of an anti - psoriasis effective amount of doxivir is discloses .

Description:
1 . it was recently discovered that the transcription factor zinc - finger protein gli - similar ( glisl ) is found only in psoriatic and not in the epidermis of healthy skin 2 . the expression of this protein is restricted to the suprabasal level of the psoriatic epidermis . under experimental conditions , this transcription factor can be dramatically induced by phorbol myristate acetate ( pma ) or interferon and is thus associated with hyperplasic , inflammatory epidermis 2 . the work of nakanishi et al . suggests that glis1 is involved in the regulation of the aberrant differentiation of psoriatic epidermis . glis 1 has a unique structure containing five zinc - fingers of the cysteine 2 : histidine 2 nature 3 . doxovir ( ctc - 96 ) is an effective agent that selectively disrupts the structure and function of zinc - fingers in which the zinc is tetrahedrally coordinated to cysteines and histidines 4 . the mode of action of the drug involves displacement zinc from the protein by the axial ligation of the drug &# 39 ; s cobalt ( iii ) complex to the nitrogen of the imidazole ring of the histidine residues . the zinc - finger bearing protein is thus inactivated 4 . we have discovered that doxovir ( ctc - 96 ) will inactivate glis1 in psoriatic epidermis and as a result may selectively retard the abnormal proliferation and differentiation of psoriatic keratinocytes . 2 . there have been several reports of the possibility that human papilloma viruses ( hpvs ) are associated with at least certain manifestations of psoriasis ( e . g . 5 , 6 , 7 , 8 ). papillomaviruses proliferate and affect the differentiation and proliferation of keratinocytes . the possible role of the virus ( particularly hpv type 5 ) in the etiology or the maintenance of the abnormal differentiation of psoriatic human skin keratinocytes has thus been postulated . junb protein , a component of the ubiquitous transcription factor ap - 1 , regulates cell proliferation , differentiation , stress responses and cytokine expression in various tissues . it was found 9 that this protein is down regulated in keratinocytes of psoriatic lesions . this decrease may trigger chemokine / cytokine expression thus recruiting neutrophils and macrophages to the epidermis and thereby contributing to the phenotypic changes observed in psoriasis . several types of hpv have been shown to reduce the expression of the junb gene . it is hypothesized that hpv can , therefore , contribute to the inflammatory state of the keratinocytes in psoriatic lesions . in addition hpv interferes with keratinocyte differentiation and proliferation via the viral gene products e2 , e6 and e7 . doxovir has distinct anti - papillomavirus activity 10 , 11 the drug can reduce pathological manifestations of psoriasis that result from the activity of hpv in the psoriatic keratinocytes . 3 . one of the main features of psoriasis is severe inflammation that is usually caused by over - production of reactive oxygen species by a variety of cell types , particularly neutrophils and macrophages which penetrate the psoriatic epidermis . the evidence for this is found in psoriatic patients 12 who often have decreased antioxidant levels in their erythrocytes and other tissues 13 . thus steroids are widely used for therapy of the disease , not only to reduce auto - immune responses but also to modulate inflammatory damage caused by reactive oxygen species . the skin stage of the disease progresses to inflammatory psoriatic arthritis in 10 - 30 % of patients . it has proven to have therapeutic activity for type ii collagen - induced arthritis in mice 15 . it is , thus , suggested that doxovir ( ctc - 96 ) by virtue of its superoxide scavenging activity may be capable of alleviating some of the inflammatory phenomena associated with psoriasis . doxovir ( ctc - 96 ) is particularly advantageous in that as a new anti - psoriatic drug for the following reasons : 1 . it is efficacious against papillomaviruses . 2 . it may act effectively and specifically against a major psoriasis - associated transcription factor , glis 1 , which bears five zinc - fingers and is not found in normal skin . 3 . it may be effective in retarding or preventing psoriatic arthritis . 4 . it has no adverse effects on intact skin when given as a topical ointment . 5 . it is a unique molecule with distinct mode of action which differs from all existing psoriasis medications . ( 1 ) nickoloff , b . j . ; nestle , f . o . recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities . j . clin . invest 2004 113 , 1664 - 1675 . ( 2 ) nakanishi , g . ; kim , y . s . ; nakajima , t . ; jetten , a . m . regulatory role for kruppel - like zinc - finger protein gli - similar 1 ( glis1 ) in pma - treated and psoriatic epidermis . j invest dermatol . 2006 , 126 , 49 - 60 . ( 3 ) kim , y . s . ; nakanishi , g . ; lewandoski , m . ; jetten , a . m . glis3 , a novel member of the glis subfamily of kruppel - like zinc finger proteins with repressor and activation functions . nucleic acids res . 2003 , 31 , 5513 - 5525 . ( 4 ) louie , a . y . ; meade , t . j . a cobalt complex that selectively disrupts the structure and function of zinc fingers . proc . natl acad . sci . u . s . a . 1998 , 95 , 6663 - 6668 . 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