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n. Function of Aminoglycoside–Arginine Conjugates (AACs) as inhibitors of HIV-1 replication. 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 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 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 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 • 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 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. n. The AACs may thus represent a novel family of fusion inhibitors.

Schematic representation of the AACs Schematic representation of the AACs

Novel HIV-1 Tat Antagonists Model of the HIV-1 Tat -TAR complex 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 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, 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 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. Plausible structure of the TAR-RNA complex with Neo. R.

Pathophysiology of ADC Photomicrograph from a patient with AIDS dementia complex (ADC) shows perivascular 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, 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 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 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. 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. 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 REFERENCES

REFERENCES M. V. Catani, M. T. Corasaniti, M. Ranalli, D. Amantea, A. Litovchick, A. 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).