Function of Aminoglycoside–Arginine Conjugates (AACs) as inhibitors of HIV-1 replication.

1. Function of Aminoglycoside–Arginine Conjugates (AACs) as inhibitors of HIV-1 replication.

2. Dr. Cristina Rodriguez-Padilla • Dr. Humberto H. Lara Villegas • 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

3. Aminoglycoside–arginine conjugates (AACs) inhibit HIV-1 replication and act as Tat antagonists

4. Learning objectives : • To learn about a new potential fusion inhibitor in HIV • To learn the phases for replication of HIV • the fusion step • Tat - Tar complex • Pathophisiology of ADC • The potential neuroprotective funtion of Neor6

5. AACs compete with monoclonal antibody binding to CXCR4 • Compete with SDF-1 a and HIV-1 gp120 cellular uptake.

6. We found in the NeoR6-resistant isolates of HIV, the following mutations in gp120 and in gp41. • These findings strongly suggest that NeoR6 obstructs HIV-1 replication by interfering with the fusion step

7. The AACs may thus represent a novel family of fusion inhibitors.

9. Schematic representation of the AACs

10. Novel HIV-1 Tat Antagonists Model of the HIV-1 Tat -TAR complex

11. 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. )

12. 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).

13. Other anti-Tat functions in cell cultures and animal models are being studied. As well, are animal models for Kaposis Sarcoma ( B. Ensoli, Italy).

14. Plausible structure of the TAR-RNA complex with NeoR.

15. 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.

16. 1 ) Gp120 , 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).

17. Nerve cell "suicide" (black dots) in HIV-infected huma brain cultures (left). Nerve cells in uninfected cultures appear healthy (right). • (Courtesy of Dr. Gabuzda.)

19. Human neuroblastoma cells express CXCR4 and CCR5 chemokine receptors and that interaction between gp-120 and these receptors contributes to cytotoxicity elicited by the protein. • It has been showen the neuroprotective potential of neomycin B hexa-arginine conjugate (NeoR), a recently synthesized compound with anti-HIV activity. ( Melino et al )

20. FUNTIONS OF AACs SUMMARY • Inhibits HIV-1 replication • Tat antagonists • Bind CxCR4 • Compete with SDF-1 a and gp120 celluar utake . • NeoR6 interfere with the fusion step of HIV

21. The AACs may represent a novel family of fusion inhibitors • The NeoR6 has neuroprotective potential against gp120 triggered death • NeoR6 cross blood brain barrier

22. REFERENCES

23. 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 gp120-induced death of human neuroblastoma cells, J. Neurochem. 84, 1237-1245 (2003). • A.Lapidot, A.Litovchick, M.Eisenstein, A.Kalinkovich, G.Borkow, Neomycin B-arginine conjugate, a novel HIV-1 Tat antagonist: synthesis and anti-HIV activities, Antivir. Res. 53 (3): 26 Sp. Iss. (2002).