- Количество слайдов: 23
n. Function of Aminoglycoside–Arginine Conjugates (AACs) as inhibitors of HIV-1 replication.
n Dr. Cristina Rodriguez-Padilla n Dr. Humberto H. Lara Villegas n n n Immunology and Virology Department. ( LIV). Biosecurity Laboratory level 3 ( BSL-3) Biology Faculty. ( FCB) Universidad Autonoma de Nuevo Leon (UANL). MEXICO. e-mail : dr_lara@lycos. com
Aminoglycoside–arginine conjugates (AACs) inhibit HIV-1 replication and act as Tat antagonists
Learning objectives : To learn about a new potential fusion inhibitor in HIV n To learn the phases for replication of HIV n the fusion step n Tat - Tar complex n Pathophisiology of ADC n The potential neuroprotective funtion of Neor 6 n
• AACs compete with monoclonal antibody binding to CXCR 4 n. Compete with SDF-1 a and HIV-1 gp 120 cellular uptake.
n. We found in the Neo. R 6 -resistant isolates of HIV, the following mutations in gp 120 and in gp 41. n. These findings strongly suggest that Neo. R 6 obstructs HIV-1 replication by interfering with the fusion step
n. The AACs may thus represent a novel family of fusion inhibitors.
Schematic representation of the AACs
Novel HIV-1 Tat Antagonists Model of the HIV-1 Tat -TAR complex
n. Targeted against transcription transactivator protein (Tat ) (AACs) are being studied with the aim of understanding the mechanisms of inhibition of the diversity functions of Tat protein, which might be critical for anti-AIDS strategies. ( Lapidot A. and cols. )
n. This AACs revealed antiviral activity in cell cultures and inhibited viral-host cell fusion, as well as binding to TAR-RNA (with G. Borkow , Lapidot A. in Israel, J. Este, Spain, C. Rodriguez and H. Lara , Mexico).
n Other anti-Tat functions in cell cultures and animal models are being studied. As well, are animal models for Kaposis Sarcoma ( B. Ensoli, Italy).
Plausible structure of the TAR-RNA complex with Neo. R.
Pathophysiology of ADC Photomicrograph from a patient with AIDS dementia complex (ADC) shows perivascular and parenchymal infiltrates of lymphocytes and macrophages. These often form microglial nodules.
1 ) Gp 120, may be shed by an infected macrophage in the brain, causing damage to nerve cells. 2 ) The HIV TAT gene, a protein that helps in the production of new virus, detaches from HIV and circulates in the blood, causing toxic effects in nerve cells (neurotoxic).
n Nerve cell "suicide" (black dots) in HIVinfected huma brain cultures (left). Nerve cells in uninfected cultures appear healthy (right). n (Courtesy of Dr. Gabuzda. )
n. Human neuroblastoma cells express CXCR 4 and CCR 5 chemokine receptors and that interaction between gp-120 and these receptors contributes to cytotoxicity elicited by the protein. n. It has been showen the neuroprotective potential of neomycin B hexa-arginine conjugate (Neo. R), a recently synthesized compound with anti-HIV activity. ( Melino et al )
FUNTIONS OF AACs SUMMARY n Inhibits HIV-1 replication n Tat antagonists n Bind Cx. CR 4 n Compete with SDF-1 a and gp 120 celluar utake. n Neo. R 6 interfere with the fusion step of HIV
n. The AACs may represent a novel family of fusion inhibitors n. The Neo. R 6 has neuroprotective potential against gp 120 triggered death n. Neo. R 6 cross blood brain barrier
REFERENCES M. V. Catani, M. T. Corasaniti, M. Ranalli, D. Amantea, A. Litovchick, A. Lapidot and G. Melino, The Tat antagonist neomycin B hexa-arginine conjugate inhibits gp 120 induced death of human neuroblastoma cells, J. Neurochem. 84, 1237 -1245 (2003). A. Lapidot, A. Litovchick, M. Eisenstein, A. Kalinkovich, G. Borkow, Neomycin Barginine conjugate, a novel HIV-1 Tat antagonist: synthesis and anti-HIV activities, Antivir. Res. 53 (3): 26 Sp. Iss. (2002).