A tetramer model for HIV-1 IN with DNA representing the LTR termini was previously assembled to predict the IN residues that interact with the LTR termini; these predictions were experimentally verified for nine amino acid residues (Chen et al, J. Biol. Chem. 281, 4173-4182 (2006)). In a similar strategy the unique amino acids found in ASV IN rather than HIV-1 or MPMV IN were substituted into the structurally related positions of HIV-1 IN. Substitutions of six additional residues (Q44, L68, E69, D229, S230 and D253) showed changes in the 3′ processing specificity of the enzyme verifying their predicted interaction with the LTR DNA. The newly identified residues extend interactions along a sixteen base pair length of the LTR termini and are consistent with known LTR DNA: HIV-1 IN cross-links. The tetramer model for HIV-1 IN with LTR termini was modified to include two IN binding domains for LEDGF/p75. The target DNA was predicted to bind in a surface trench perpendicular to the plane of the LTR DNA binding sites of HIV-1 IN and extending alongside LEDGF. This hypothesis is supported by the in vitro activity phenotype of HIV-1 IN mutant with a K219S substitution showing loss in strand transfer activity while maintaining 3′ processing on a HIV-1 substrate. Mutations at seven other residues reported in the literature have the same phenotype and all eight residues align along the length of the putative target DNA binding trench.
This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.
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