Spring 2011 Biomedical Seminar Series
DESUMOYLATION ENZYMES ARE ASSOCIATED WITH THE INHIBITORY EFFECTS OF A SMALL MOLECULE ON HIV-1.
Dr. IKENNA MADU
Department of Molecular Medicine, Beckman Research Center, City of Hope, Duarte CA 91010
Small ubiquitin-like modifier (SUMO) conjugates to proteins and affects proteinÂprotein interactions, intracellular localization, or directs changes in the activities of the protein, making it an ideal target for novel therapeutics for cancer and infectious diseases. Here, we describe NSC 5068 a non-cytotoxic small molecule, identified in high-throughput screens as an inhibitor of both HIV and SUMO de-conjugation proteases (SENP). Time-of-addition, integration via Alu-based PCR, and Tat dependent transcription assays suggest that the inhibition does not occur at the entry stage. Interestingly, electron microscopy analysis of virus budding revealed a malfunction in the assembly of virus particles generated in the presence of the inhibitor. This was also supported by the reduction in infectivity observed with viral luciferase reporter systems and latency models. These results indicate that SUMO proteases may play an important role for virus maturation and infectivity through an undetermined mechanism.
1. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets.Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE. Nat Rev Drug Discov. 2011 Jan;10(1):29-46. Epub 2010 Dec 10. Review.
2. Nuclear and unclear functions of SUMO. Seeler JS, Dejean A. Nat Rev Mol Cell Biol. 2003 Sep;4(9):690-9. Review.
3. The in vivo functions of desumoylating enzymes. Bawa-Khalfe T, Yeh ET. Subcell Biochem. 2010;54:170-83.
4. Curing HIV: Pharmacologic approaches to target HIV-1 latency. Choudhary SK, Margolis DM. Annu Rev Pharmacol Toxicol. 2011 Feb 10;51:397-418.
5. Viruses and sumoylation: recent highlights. Boggio R, Chiocca S. Curr Opin Microbiol. 2006 Aug;9(4):430-6. Epub 2006 Jul 3. Review.
6. Covalent modification of human immunodeficiency virus type 1 p6 by SUMO-1. Gurer C, Berthoux L, Luban J. J Virol. 2005 Jan;79(2):910-7.
7. Human Ubc9 contributes to production of fully infectious human immunodeficiency virus type 1 virions. Jaber T, Bohl CR, Lewis GL, Wood C, West JT Jr, Weldon RA Jr. J Virol. 2009 Oct;83(20):10448-59. Epub 2009 Jul 29.