Albert Einstein College of Medicine

Columbia University

Ganjam V Kalpana

William R Jacobs, Jr

Barry R Bloom

Stephen P Goff

Ruth McAdam

Jeffrey D Cirillo

Bhaskar C Das

Synthetic peptidomimetic derivatives and phenyl group derivatives of Fenretinide (4-HPR) are disclosed, as are their uses as therapeutic, diagnostic and imaging agents for cancer and other diseases.

Fenretinide derivatives and uses thereof as therapeutic, diagnostic and imaging agents

Peptides comprising an Rpt1 domain of an INI1/hSNF5 which inhibit HIV-1 production in a human cell, and vectors encoding those peptides are provided. Also provided are methods of inhibiting HIV-1 production in a cell, or spread of the HIV-1 to another cell, by treating the cells with the above peptides or vectors. Other methods of inhibiting HIV-1 production in a cell, or spread of the HIV-1 to another cell, by inhibiting production of INI1/hSNF5 are provided. Additionally, methods of determining whether a test compound inhibits HIV-1 virion production in a mammalian cell, or spread of the HIV-1 to another cell, are provided. Those methods comprise determining whether the test compound inhibits the production of INI1/hSNF5 or disrupts the interaction of HIV-1 integrase with INI1/hSNF5.

Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1 (INI1)/hSNF5

Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1(INI1)/hSNF5

A mutated mycobacterium selected from the class consisting of mutated -BCG, mutated and mutated . The mutation of -BCG, or is preferably effected through an insertional mutation of a mycobacterial gene. The insertional mutagenesis may be effected, for example, through illegitimate recombination or by a mycobacterial transposon. Such mutated mycobacteria may then be transformed with an expression vector(s) containing a complement gene to the gene which is mutated, and preferably also including a heterologous gene.

Insertional mutations in mycobacteria

A mutated mycobacterium selected from the class consisting of mutated -BCG, mutated and mutated The mutation of -BCG, or is preferably effected through an insertional mutation of a mycobacterial gene. The insertional mutagenesis may be effected, for example, through illegitimate recombination or by a mycobacterial transposon. Such mutated mycobacteria may then be transformed with an expression vector(s) containing a complement gene to the gene which is mutated, and preferably also including a heterologous gene.

Upon entry into a host cell, retroviruses direct the reverse transcription of the viral RNA genome and the establishment of an integrated proviral DNA. The retroviral integrase protein (IN) is responsible for the insertion of the viral DNA into host chromosomal targets. The IN catalyzes two specific biochemical reactions: (i) cleavage of the 3&prime;termini of the viral DNA to produce 3&prime;-OH ends, and (ii) joining of the two newly generated 3&prime;-termini to the 5&prime;-phosphates on each strand of the target sequence in a concerted strand-transfer reaction. The yeast two-hybrid system was used to identify a novel human gene product, herein designated integrase interactor 1 or INI-1, that binds tightly to the human immunodeficiency virus type 1 (HIV-1) integrase in vitro. Approximately 10,complementary DNAs (cDNAs) of the HL60 macrophage-monocytic cell line were expressed as GAL4AC (activation domain) fusions and tested for coactivation of a reporter gene together with a GAL4DB (DNA binding) IN fusion. Overlapping cDNA clones were identified and their nucleotide sequences ascertained. Nucleotide sequence analysis revealed that INI-1 displays limited amino acid homology to the yeast SNF5 protein, a transcriptional activator required for high-level expression of many disparate cellular genes. Nucleotide sequences encoding the INI-1 gene product will prove useful for the generation of biochemical reagents and the development novel HIV-1 antiviral agents.

Nucleic acids encoding a human immunodeficiency virus type 1 (HIV-1) integrase interactor protein (INI-1)

Upon entry into a host cell, retroviruses direct the reverse transcription of the viral RNA genome and the establishment of an integrated proviral DNA. The retroviral integrase protein (IN) is responsible for the insertion of the viral DNA into host chromosomal targets. The IN catalyzes two specific biochemical reactions: (i) cleavage of the 3'termini of the viral DNA to produce 3'-OH ends, and (ii) joining of the two newly generated 3'-termini to the 5'-phosphates on each strand of the target sequence in a concerted strand-transfer reaction. The yeast two-hybrid system was used to identify a novel human gene product, herein designated integrase interactor 1 or INI-1, that binds tightly to the human immunodeficiency virus type 1 (HIV-1) integrase in vitro. Approximately 10.sup.6 complementary DNAs (cDNAs) of the HL60 macrophage-monocytic cell line were expressed as GAL4AC (activation domain) fusions and tested for coactivation of a reporter gene together with a GAL4DB (DNA binding) IN fusion. Overlapping cDNA clones were identified and their nucleotide sequences ascertained. Nucleotide sequence analysis revealed that INI-1 displays limited amino acid homology to the yeast SNF5 protein, a transcriptional activator required for high-level expression of many disparate cellular genes. The INI-1 gene product will prove useful for the generation of biochemical reagents and the development novel HIV-1 antiviral agents.

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Yonkers, NY, United States of America

Ganjam V Kalpana