Papillomaviruses (HPVs) are a major cause of @entity1 disease, and are responsible for approximately half a million cases of @entity5 each year. HPVs also cause genital warts, and are the most common @entity2953 in many countries. Despite their importance, there are currently no specific antivirals that are active against HPVs. Papillomavirus protein function is mediated largely by protein-protein interactions, which are difficult to inhibit using conventional approaches. To circumvent these problems, we have prepared an @entity10390 library, and have used this to isolate high-affinity binding molecules that may stearically hinder the association of E6 with @entity876 and prevent E6-mediated @entity876 degradation in @entity5 cells. One of the molecules isolated from the library (GTE6-1), had an affinity for 16E6 of 60nM, and bound within the first zinc finger of the protein. GTE6-1 was able to associate with non-denatured E6 following expression in @entity1 cells and could inhibit E6-mediated @entity876 degradation in in vitro assays. E6-mediated @entity876 degradation is essential for the continuous growth of @entity5 cells caused by @entity1799 . To examine the potential of GTE6-1 as an inhibitor of E6 function in such cells, the molecule was expressed in @entity10390 , diabody and triabody formats in a number of cell lines that are driven to proliferate by the @entity1799 oncogenes E6 and E7, including the @entity5 cell line SiHa. In contrast to small E6-binding peptides containing the ELLG E6-binding motif, GTE6-1 expression lead to changes in nuclear structure, the appearance of apoptosis markers, and an elevation in the levels of @entity876 . No effects were seen with a control @entity10390 molecule, or when GTE6-1 was expressed in cells that are driven to proliferate by @entity2235 (SV40) T-antigen. Given the accessibility of HPV-associated lesions to topical therapy, our results suggest that large interfering molecules such as intrabodies may be useful inhibitors of viral protein-protein interactions and be particularly appropriate for the treatment of @entity66 .

Inhibition of papillomavirus protein function in XXXX cells by intrabody targeting.

@entity1 :: ('9606', 'Species') :: ['mammalian', 'human'] @entity2953 :: ('MESH:D012749', 'Disease') :: ['sexually transmitted disease'] @entity2235 :: ('10633', 'Species') :: ['simian virus 40'] @entity66 :: ('MESH:D004194', 'Disease') :: ['HPV-associated disease'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cervical cancer'] @entity876 :: ('7157', 'Gene') :: ['p53'] @entity1799 :: ('333760', 'Species') :: ['HPV16'] @entity10390 :: ('652070', 'Gene') :: ['scFv']
@entity5 :: (MESH:D009369,Disease) :: ['cervical cancer']
