Fragment hopping approach directed at design of HIV IN-LEDGF/p75 interaction inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Volumn 28, Issue 5, 2013, Pages 1002-1009

  De Luca, Laura ^a   Ferro, Stefania ^a   Morreale, Francesca ^a   Christ, Frauke ^b   Debyser, Zeger ^b   Chimirri, Alba ^a   Gitto, Rosaria ^a  

^a UNIVERSITY OF MESSINA   (Italy)

^b UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

HIV; IN LEDGF p75; Indoles; Microwave assisted synthesis; Protein protein interactions

Indexed keywords

1 (1H INDOLE 3 CARBONYL)PYRROLIDINE 2 CARBOXYLIC ACID; 1 (4 HYDROXY 1H INDOLE 3 CARBONYL)PYRROLIDINE 2 CARBOXYLIC ACID; 1 (4 METHOXY 1H INDOLE 3 CARBONYL) PYRROLIDINE 2 CARBOXYLIC ACID; 1 [1 (3,5 DIMETHYLBENZYL) 1H INDOLE 3 CARBONYL] PYRROLIDINE 2 CARBOXYLIC ACID; 1 [1 (3,5 DIMETHYLBENZYL) 4 HYDROXY 1H INDOLE 3 CARBONYL] PYRROLIDINE 2 CARBOXYLIC ACID; 1 [1 (3,5 DIMETHYLBENZYL) 4 METHOXY 1H INDOLE 3 CARBONYL] PYRROLIDINE 2 CARBOXYLIC ACID; 1 [1 (4 FLUOROBENZYL) 1H INDOLE 3 CARBONYL]PYRROLIDINE 2 CARBOXYLIC ACID; 1 [1 (4 FLUOROBENZYL) 4 HYDROXY 1H INDOLE 3 CARBONYL] PYRROLIDINE 2 CARBOXYLIC ACID; 1 [1 (4 FLUOROBENZYL) 4 METHOXY 1H INDOLE 3 CARBONYL] PYRROLIDINE 2 CARBOXYLIC ACID; 2 (1H INDOLE 3 CARBOXAMIDO)ACETIC ACID; 2 (4 HYDROXY 1H INDOLE 3 CARBOXAMIDO)ACETIC ACID; 2 (4 METHOXY 1H INDOLE 3 CARBOXAMIDO)ACETIC ACID; 2 [1 (3,5 DIMETHYLBENZYL) 1H INDOLE 3 CARBOXAMIDO]ACETIC ACID; 2 [1 (3,5 DIMETHYLBENZYL) 4 HYDROXY 1H INDOLE 3 CARBOXAMIDO]ACETIC ACID; 2 [1 (3,5 DIMETHYLBENZYL) 4 METHOXY 1H INDOLE 3 CARBOXAMIDO]ACETIC ACID; 2 [1 (4 FLUOROBENZYL) 1H INDOLE 3 CARBOXAMIDO]ACETIC ACID; 2 [1 (4 FLUOROBENZYL) 4 METHOXY 1H INDOLE 3 CARBOXAMIDO]ACETIC ACID; 2 [1(4 FLUOROBENZYL) 4 HYDROXY 1H INDOLE 3 CARBOXAMIDO] ACETIC ACID; INDOLE DERIVATIVE; INTEGRASE; LENS EPITHELIUM DERIVED GROWTH FACTOR; PROTEIN P75; SMALL MOLECULE TRANSPORT AGENT; UNCLASSIFIED DRUG;

ARTICLE; BIOLOGICAL FUNCTIONS; CHEMICAL STRUCTURE; CHROMATOGRAPHY; CRYSTAL STRUCTURE; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS; MUTAGENESIS; PHARMACOPHORE; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION;

DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; KETO ACIDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84884231563     PISSN: 14756366     EISSN: 14756374     Source Type: Journal    
DOI: 10.3109/14756366.2012.703184     Document Type: Article

References (26)

1. Le Douce V, Janossy A, Hallay H, Ali S, Riclet R, Rohr O et al. Achieving a cure for HIV infection: do we have reasons to be optimistic? J Antimicrob Chemother 2012;67:1063-1074.
2. Esté JA, Cihlar T. Current status and challenges of antiretroviral research and therapy. Antiviral Res 2010;85:25-33.
3. Sechi M, Rizzi G, Bacchi A, Carcelli M, Rogolino D, Pala N et al. Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors. Bioorg Med Chem 2009;17:2925-2935.
4. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH et al. An essential role for LEDGF/p75 in HIV integration. Science 2006;314:461-464.
5. Hombrouck A, De Rijck J, Hendrix J, Vandekerckhove L, Voet A, De Maeyer M et al. Virus evolution reveals an exclusive role for LEDGF/ p75 in chromosomal tethering of HIV. PLoS Pathog 2007;3:e47.
6. Llano M, Morrison J, Poeschla EM. Virological and cellular roles of the transcriptional coactivator LEDGF/p75. Curr Top Microbiol Immunol 2009;339:125-146.
7. Al-Mawsawi LQ, Neamati N. Blocking interactions between HIV-1 integrase and cellular cofactors: An emerging anti-retroviral strategy. Trends Pharmacol Sci 2007;28:526-535.
8. Craigie R. Targeting HIV-1 DNA integration by swapping tethers. Proc Natl Acad Sci USA 2010;107:2735-2736.
9. Busschots K, Voet A, De Maeyer M, Rain JC, Emiliani S, Benarous R et al. Identification of the LEDGF/p75 binding site in HIV-1 integrase. J Mol Biol 2007;365:1480-1492.
10. Greene WC, Debyser Z, Ikeda Y, Freed EO, Stephens E, Yonemoto W et al. Novel targets for HIV therapy. Antiviral Res 2008;80:251-265.
11. Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol 2005;12:526-532.
12. Al-Mawsawi LQ, Neamati N. Allosteric inhibitor development targeting HIV-1 integrase. ChemMedChem 2011;6:228-241.
13. Hayouka Z, Hurevich M, Levin A, Benyamini H, Iosub A, Maes M et al. Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein. Bioorg Med Chem 2010;18:8388-8395.
14. Hayouka Z, Levin A, Maes M, Hadas E, Shalev DE, Volsky DJ et al. Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370. Biochem Biophys Res Commun 2010;394:260-265.
15. Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D et al. Rational design of small-molecule inhibitors of the LEDGF/p75- integrase interaction and HIV replication. Nat Chem Biol 2010;6:442-448.
16. De Luca L, Barreca ML, Ferro S, Christ F, Iraci N, Gitto R et al. Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. ChemMedChem 2009;4:1311-1316.
17. De Luca L, Gitto R, Christ F, Ferro S, De Grazia S, Morreale F et al. 4-[1-(4-Fluorobenzyl)-4-hydroxy-1H-indol-3-yl]-2-hydroxy-4- oxobut-2-enoic acid as a prototype to develop dual inhibitors of HIV-1 integration process. Antiviral Res 2011;92:102-107.
18. De Luca L, Ferro S, Gitto R, Barreca ML, Agnello S, Christ F et al. Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg Med Chem 2010;18:7515-7521.
19. Accelrys. Catalyst. San Diego, CA: Accelrys, Inc. Available at: Http://www.accelrys.com
20. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997;267:727-748.
21. Barreca ML, Rao A, De Luca L, Zappalà M, Gurnari C, Monforte P et al. Efficient 3D database screening for novel HIV-1 IN inhibitors. J Chem Inf Comput Sci 2004;44:1450-1455.
22. Al-Mawsawi LQ, Christ F, Dayam R, Debyser Z, Neamati N. Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: insight into integrase- DNA complex formation and catalysis. FEBS Lett 2008;582:1425-1430.
23. De Luca L, Ferro S, Morreale F, Chimirri A. Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: A promising approach in anti-retroviral therapy. Mini Rev Med Chem 2011;11:714-727.
24. De Luca L, Ferro S, Morreale F, De Grazia S, Chimirri A. Inhibitors of the interactions between HIV-1 IN and the cofactor LEDGF/p75. ChemMedChem 2011;6:1184-1191.
25. Rao A, Chimirri A, Ferro S, Monforte AM, Monforte P, Zappalà M. Microwave-assisted synthesis of benzimidazole and thiazolidinone derivatives as HIV-1 RT inhibitors. Arkivoc 2004;part(v):147-155.
26. Ferro S, De Luca L, Barreca ML, De Grazia S, Christ F, Debyser Z et al. New chloro, fluorobenzylindole derivatives as integrase strandtransfer inhibitors (INSTIs) and their mode of action. Bioorg Med Chem 2010;18:5510-5518.