Extracts from medicinal plants indigenous to China have been used for centuries to treat a variety of ailments including viral infections, tumors, heart conditions and the termination of pregnancy. There is new found interest in these extracts as their biological activities have been clearly established in controlled clinical studies and their active ingredients identified and isolated.

Description of the Project:
Dr. Lee-Huang and her coworkers have identified, purified, cloned and characterized a new class of potent anti-HIV agents with multiple therapeutic targets. Two of the lead compounds are MAP 30 (Momordica Anti-HIV Protein, 30 KDa) from the seeds of Momordica charantia, commonly known as the bitter melon (Lee-Huang, et al FEBS Lett 1990; 272: 12-18) and GAP 31 (Gelonium Anti-HIV Protein, 31 KDa) from the seeds of Gelonium multiflorum (Lee-Huang, et al FEBS Lett 1991; 291: 139-144).

MAP30 and GAP31 are unique in that they inhibit not only de novo infection by HIV-1 but also block the replication of the virus in already infected cells. These compounds affect the HIV-1 at levels that exhibit no toxic effects on normal human cells and in intact animals. The Anti-Cancer Drug Screening Program of the National Cancer Institute (NCI) has identified potent anti-tumor activity (Int. J. Onc. 1994; 5: 1171-1176). Subsequent animal studies by NCI Tumor treatment Division demonstrated that MAP30 and GAP31 are efficacious for human breast tumor cells in vivo (Lee-Huang, S. et.al. Anticancer Research 2000; 20: 653).

Dr. Lee-Huang and collaborators have identified at least three activities that may be important to the antiviral action of MAP30 and GAP31: The first is a DNA glycosylase/ap lyase activity that inhibits HIV-integrase (Cell 1999; 99: 433-442, Nature Structural Biology 2000; 7: 17-18 and Proc. Natl. Acad. Sci. USA 1995; 92: 8818-8822). The second is a DNA topological inactivation activity that renders HIV-LTR DNA topologically inactive (Biofactors 1992; 4: 37-42 and Proc. Natl. Acad. Sci. USA 1995; 92: 8818-8822). The third is an RNA N-glycosidase activity that inactivates the 60S ribosomal subunit and inhibits polypeptide chain elongation.

To define the roles of the various activities of MAP30 and GAP31 in antiviral and anti-tumor actions, Dr. Lee-Huang et al carried out structure-activity mapping of these compounds by proteolytic fragmentation, molecular modeling and bioinformatics. They identified and isolated peptide fragments that are devoid of RNA N-glycosidase activity (ribosome inactivation) but active against HIV-1 and human tumors (BBRC, 1999; 262: 615-623, Proc. Natl. Acad. Sci. USA 1994; 91: 12208-12212) as well as specific domains / motifs critical for HIV-1 inhibition (Cell 1999; 99: 433-442, Nature Structural Biology 2000; 7: 17-18).

MAP30 and GAP31 are also effective against HSV-1, HSV-2 (BBRC 1996; 219: 923-929), CMV, and HHV8 (BBRC 2001; 287(4): 983-94). They down-regulate the expression of viral genes vCD, vIL-6 and v-Flip as were as modulate the expression profile of cellular genes for proliferation and apoptosis. Thus, these compounds are also potentially useful for combined therapy against HIV-1 and AIDS-related tumors infected with the KS virus.

Applications:
NYU is seeking a partner to develop these proteins as anti-tumor, anti-viral and anti-HIV therapeutic agents.

Patent Status:

Patent applications have been awarded.