Single amino acid substitution in HIV-1 integrase catalytic core causes a dramatic shift in inhibitor selectivity

FEBS Letters

Volumn 581, Issue 6, 2007, Pages 1151-1156

  Al Mawsawi, Laith Q ^a   Sechi, Mario ^b   Neamati, Nouri ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b UNIVERSITY OF SASSARI   (Italy)

Author keywords

3 Processing; HIV 1; Integrase; Strand transfer

Indexed keywords

1 [5 (4 FLUOROBENZYL) 2 FURYL] 3 (1,2,4 TRIAZOL 3 YL) 1,3 PROPANEDIONE; COMPLEMENTARY DNA; INTEGRASE; INTEGRASE INHIBITOR; SERINE;

AMINO ACID SUBSTITUTION; ARTICLE; CATALYSIS; CONTROLLED STUDY; DRUG STRUCTURE; ENZYME ACTIVE SITE; ENZYME CONFORMATION; ENZYME INHIBITION; ENZYME MECHANISM; ENZYME SPECIFICITY; GENOME; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; PRIORITY JOURNAL; VIRUS DNA CELL DNA INTERACTION; VIRUS REPLICATION;

AMINO ACID SUBSTITUTION; BINDING SITES; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HUMANS; PROTEIN CONFORMATION; SERINE; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 33847746306     PISSN: 00145793     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.febslet.2007.02.023     Document Type: Article

References (20)

1. Brown P.O. Integration. In: Coffin J.M., Hughes S.H., and Varmus H.E. (Eds). Retroviruses (1997), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY 161-203
2. Bushman F.D., and Craigie R. Activities of human immunodeficiency virus (HIV) integration protein in vitro: specific cleavage and integration of HIV DNA. Proc. Natl. Acad. Sci. USA 88 (1991) 1339-1343
3. Dayam R., Deng J., and Neamati N. HIV-1 integrase inhibitors: 2003-2004 update. Med. Res. Rev. 26 (2006) 271-309
4. Neamati N. Patented small molecule inhibitors of HIV-1 integrase: a 10-year saga. Expert Opin. Ther. Pat. 12 (2002) 709-724
5. Pommier Y., Johnson A.A., and Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat. Rev. Drug Discov. 4 (2005) 236-248
6. Marchand C., et al. Metal-dependent inhibition of HIV-1 integrase by β-diketo acids and resistance of the soluble double-mutant (F185K/C280S). Mol. Pharmacol. 64 (2003) 600-609
7. Zhu K., Dobard C., and Chow S.A. Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase. J. Virol. 78 (2004) 5045-5055
8. Al-Mawsawi L.Q., Fikkert V., Dayam R., Witvrouw M., Burke Jr. T.R., Borchers C.H., and Neamati N. Discovery of a small-molecule HIV-1 integrase inhibitor-binding site. Proc. Natl. Acad. Sci. USA 103 (2006) 10080-10085
9. Jenkins T.M., Engelman A., Ghirlando R., and Craigie R. A soluble active mutant of HIV-1 integrase: involvement of both the core and carboxyl-terminal domains in multimerization. J. Biol. Chem. 271 (1996) 7712-7718
10. Sechi M., Angotzi G., Dallocchio R., Dessi A., Carta F., Sannia L., Mariani A., Fiori S., Sanchez T., Movsessian L., Plasencia C., and Neamati N. Design and synthesis of novel dihydroxyindole-2-carboxylic acids as HIV-1 integrase inhibitors. Antivir. Chem. Chemother. 15 (2004) 67-81
11. Dayam R., Sanchez T., Clement O., Shoemaker R., Sei S., and Neamati N. β-Diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors. J. Med. Chem. 48 (2005) 111-120
12. Billich A. S-1360 Shionogi-GlaxoSmithKline. Curr. Opin. Investig. Drugs 4 (2003) 206-209
13. Yoshinaga, T., Sato, A., Fujishita, T. and Fujiwara, T. (2002) S-1360: In vitro activity of a new HIV-1 integrase inhibitor in clinical development. In: Proceedings of the Ninth International Conference Retroviruses Opportunistic Infect.
14. Rosemond M.J., St John-Williams L., Yamaguchi T., Fujishita T., and Walsh J.S. Enzymology of a carbonyl reduction clearance pathway for the HIV integrase inhibitor, S-1360: role of human liver cytosolic aldo-keto reductases. Chem. Biol. Interact. 147 (2004) 129-139
15. Zhao H., Neamati N., Sunder S., Hong H., Wang S., Milne G.W., Pommier Y., and Burke Jr. T.R. Hydrazide-containing inhibitors of HIV-1 integrase. J. Med. Chem. 40 (1997) 937-941
16. Zawahir Z., and Neamati N. Inhibition of HIV-1 integrase activity by synthetic peptides derived from the HIV-1 HXB2 Pol region of the viral genome. Bioorg. Med. Chem. Lett. 16 (2006) 5199-5202
17. Goldgur Y., Dyda F., Hickman A.B., Jenkins T.M., Craigie R., and Davies D.R. Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. Proc. Natl. Acad. Sci. USA 95 (1998) 9150-9154
18. Petit C., Schwartz O., and Mammano F. Oligomerization within virions and subcellular localization of human immunodeficiency virus type 1 integrase. J. Virol. 73 (1999) 5079-5088
19. Lu R., Limon A., Devroe E., Silver P.A., Cherepanov P., and Engelman A. Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a postnuclear entry step of human immunodeficiency virus type 1 replication. J. Virol. 78 (2004) 12735-12746
20. Bischerour J., Leh H., Deprez E., Brochon J.C., and Mouscadet J.F. Disulfide-linked integrase oligomers involving C280 residues are formed in vitro and in vivo but are not essential for human immunodeficiency virus replication. J. Virol. 77 (2003) 135-141