Determinants for sensitivity of human immunodeficiency virus coreceptor CXCR4 to the bicyclam AMD3100.

Journal of Virology
B LabrosseM Alizon

Abstract

The bicyclam AMD3100 is a potent and selective inhibitor of the replication of human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2). It was recently demonstrated that the compound inhibited HIV entry through CXCR4 but not through CCR5. Selectivity of AMD3100 for CXCR4 was further indicated by its lack of effect on HIV-1 and HIV-2 infection mediated by the CCR5, CCR3, Bonzo, BOB, and US28, coreceptors. AMD3100 completely blocked HIV-1 infection mediated by a mutant CXCR4 bearing a deletion of most of the amino-terminal extracellular domain. In contrast, relative resistance to AMD3100 was conferred by different single amino acid substitutions in the second extracellular loop (ECL2) or in the adjacent membrane-spanning domain, TM4. Only substitutions of a neutral residue for aspartic acid and of a nonaromatic residue for phenylalanine (Phe) were associated with drug resistance. This suggests a direct interaction of AMD3100 with these amino acids rather than indirect effects of their mutation on the CXCR4 structure. The interaction of aspartic acids of ECL2 and TM4 with AMD3100 is consistent with the positive charge of bicyclams, which might block HIV-1 entry by preventing electrostatic interactions between CXCR4 and th...Continue Reading

References

Jun 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·E De ClercqD Schwartz
Apr 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·P WesterveltL Ratner
Oct 13, 1995·The Journal of Biological Chemistry·E O Freed, M A Martin
Apr 1, 1994·Antimicrobial Agents and Chemotherapy·E De ClercqR Datema
Apr 1, 1994·Current Opinion in Cell Biology·J M Baldwin
Feb 1, 1994·Journal of Virology·F Clavel, P Charneau
Apr 15, 1997·Proceedings of the National Academy of Sciences of the United States of America·A L EdingerR W Doms
Aug 1, 1997·Current Opinion in Immunology·J P MooreT Dragic
Oct 23, 1997·The Journal of Experimental Medicine·D ScholsE De Clercq
Oct 23, 1997·The Journal of Experimental Medicine·T MurakamiT Nagasawa
Jan 14, 1998·Nature Medicine·G A DonzellaJ P Moore
May 16, 1998·Current Biology : CB·N HevekerJ Schneider-Mergener

❮ Previous
Next ❯

Citations

Jun 27, 2012·The Journal of Biological Chemistry·Lusine H DemirkhanyanGregory B Melikyan
Jul 18, 2001·The Journal of General Virology·T Dragic
Dec 28, 2002·Journal of Virology·Béatrice LabrosseFabrizio Mammano
Sep 11, 2002·FEBS Letters·Sigrid HatseDominique Schols
Sep 22, 2005·Acta Pharmacologica Sinica·Elias KrambovitisDemetrios A Spandidos
May 19, 2007·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Manit AryaHiten R H Patel
Oct 3, 2006·Annual Review of Pharmacology and Toxicology·Lauren T MayArthur Christopoulos
Apr 19, 2016·Current Pharmacology Reports·Yan WangDavid Oupický
Apr 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·T DragicJ P Moore
Sep 10, 2002·AIDS·Julio Martín-GarcíaFrancisco González-Scarano
Sep 24, 2004·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Craig W HendrixUNKNOWN AMD3100 HIV Study Group
Oct 9, 2002·Medicinal Research Reviews·Erik De Clercq
Nov 16, 2004·Journal of Virology·Katrien PrincenDominique Schols
Oct 20, 2010·The Journal of Biological Chemistry·Stéphanie GravelNikolaus Heveker
Jul 17, 2010·Future Microbiology·Tsutomu Murakami, Naoki Yamamoto

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.