Inhibitors of HIV-1 protease by using in situ click chemistry

Angewandte Chemie - International Edition

Volumn 45, Issue 9, 2006, Pages 1435-1439

  Whiting, Matthew ^a   Muldoon, John ^a   Lin, Ying Chuan ^a   Silverman, Steven M ^a   Lindstrom, William ^a   Olson, Arthur J ^a   Kolb, Hartmuth C ^a   Finn, M G ^a   Sharpless, K Barry ^a   Elder, John H ^a   Fokin, Valery V ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

Click chemistry; Drug design; HIV 1 protease; Inhibitors; Triazoles

Indexed keywords

CLICK CHEMISTRY; DRUG DESIGN; HIV-1 PROTEASE; INHIBITORS; TRIAZOLES;

BINDERS; OLEFINS; REACTION KINETICS; STEREOCHEMISTRY;

PROTEINS;

HUMAN IMMUNODEFICIENCY VIRUS PROTEINASE INHIBITOR; PROTEINASE INHIBITOR;

ARTICLE; CHEMISTRY; COMBINATORIAL CHEMISTRY; CONFORMATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; METHODOLOGY; SENSITIVITY AND SPECIFICITY; STEREOISOMERISM; SYNTHESIS; TIME;

CHROMATOGRAPHY, HIGH PRESSURE LIQUID; COMBINATORIAL CHEMISTRY TECHNIQUES; HIV PROTEASE INHIBITORS; MASS SPECTROMETRY; MOLECULAR CONFORMATION; SENSITIVITY AND SPECIFICITY; STEREOISOMERISM; TIME FACTORS;

EID: 33746210083     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/anie.200502161     Document Type: Article

References (33)

1. J. A. Bartlett, R. Demasi, J. Quinn, C. Moxham, F. Rousseau, AIDS 2001, 15, 1369-1377.
2. UNAIDS 2005 report, http://www.unaids.org.
3. N. E. Kohl, E. A. Emini, W. A. Schleif, L. J. Davis, J. C. Davis, J. C. Heimbach, R. A. F. Dixon, E. M. Scolnick, I. S. Sigal, Proc. Natl. Acad. Sci. USA 1988, 85, 4686-4690.
4. J. H. Condra, W. A. Schleif, O. M. Blahy, L. J. Gabryelski, D. J. Graham, J. C. Quintero, A. Rhodes, H. L. Robbins, E. Roth, M. Shivaprakash, Nature 1995, 374, 569-571.
5. a) D. Rideout, Science 1986, 233, 561-563;
6. b) D. Rideout, T. Calogeropoulou, J. Jaworski, M. McCarthy, Biopolymers 1990, 29, 247-262;
7. c) O. Ramstrom, J.-M. Lehn, Nat. Rev. Drug Discovery 2002, 1, 26-36, and references therein;
8. d) S. Otto, Curr. Opin. Drug Discovery Dev. 2003, 6, 509-520;
9. e) D. A. Erlanson, S. K. Hansen, Curr. Opin. Chem. Biol. 2004, 8, 399-406, and references therein;
10. f) R. Nguyen, I. Huc, Angew. Chem. 2001, 113, 1824-1826;
11. Angew. Chem. Int. Ed. 2001, 40, 1774-1776;
12. g) K. C. Nicolaou, R. Hughes, S. Y. Cho, N. Winssinger, H. Labischinski, R. Endermann, Chem. Eur. J. 2001, 7, 3824-3843;
13. h) S. E. Greasley, T. H. Marsilje, H. Cai, S. Baker, S. J. Benkovic, D. L. Boger, I. A. Wilson, Biochemistry 2001, 40, 13 538-13 547, and references therein;
14. i) A. T. Poulin-Kerstien, P. B. Dervan, J. Am. Chem. Soc. 2003, 125, 15 811-15 821.
15. a) W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radic, P. R. Carlier, P. Taylor, M. G. Finn, K. B. Sharpless, Angew. Chem. 2002, 114, 1095-1099;
16. Angew. Chem. Int. Ed. 2002, 41, 1053-1057;
17. b) R. Manetsch, A. Krasinski, Z. Radic, J. Raushel, P. Taylor, K. B. Sharpless, H. C. Kolb, J. Am. Chem. Soc. 2004, 126, 12 809-12 818;
18. c) V. P. Mocharla, B. Colasson, L. Lee, S. Roeper, K. B. Sharpless, C-H. Wong, H. C. Kolb, Angew. Chem. 2004, 116,118-122;
19. Angew. Chem. Int. Ed. 2005, 44, 116-120;
20. d) A. Krasinski, Z. Radic, R. Manetsch, J. Raushel, P. Taylor, K. B. Sharpless, H. C. Kolb, J. Am. Chem. Soc. 2005, 127, 6686-6692.
21. R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 (Ed.: A. Padwa), Wiley, New York, 1984, pp. 1-176.
22. R. Sanchez-Pescador, M. D. Power, P. J. Barr, K. S. Steimer, M. M. Stempien, S. L. Brown-Shimer, W. W. Gee, A. Renard, A. Randolph, J. A. Levy, D. Dina, P. A. Luciw, Science 1985, 227, 484-492.
23. a) A. Brik, J. Muldoon, Y-C. Lin, J. H. Elder, D. S. Goodsell, A. J. Olson, V. V. Fokin, K. B. Sharpless, C-H. Wong, ChemBioChem 2003, 4, 1246-1248;
24. b) A. Brik, J. Alexandratos, Y.-C. Lin, J. H. Elder, A. J. Olsen, A. Wlodawer, D. S. Goodsell, C.-H. Wong, ChemBioChem 2005, 6, 1167-1169.
25. a) C. C. Mak, V.-D. Le, Y.-C. Lin, J. H. Elder, C.-H. Wong, Bioorg. Med. Chem. Lett. 2001, 11, 219-222;
26. b) T. Lee, G. S. Laco, B. E. Torbett, H. S. Fox, D. L. Lerner, J. H. Elder, C.-H. Wong, Proc. Natl. Acad. Sci. USA 1998, 95, 939-944.
27. See the Supporting Information for full spectral details.
28. A. Adachi, H. E. Gendelman, S. Koenig, T. Folks, R. Wiley, A. Rabson, M. A. Martin, J. Virol. 1986, 284-291.
29. a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708-2711;
30. Angew. Chem. Int. Ed. 2002, 41, 2596-2599;
31. b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3064.
32. There is a possibility that potential products could be mass-spectrometry silent and thus would be left undetected if they had significantly different ionization energies. In the present study this was demonstrated not to be the case as the common azide fragment 2 gave a relatively large ESI-MS signal compared with alkyne 1 (see the Supporting Information for a more detailed explanation).
33. One advantage of the in situ click-chemistry approach over the traditional drug-discovery techniques is that the need to independently synthesize each individual compound for screening is eliminated. Increased rate of formation of a triazole product(s) indicates possible hits that can then be further investigated individually (again, very quickly thanks to the "guaranteed" nature of the cycloaddition reaction). To ascertain that no binders were overlooked in this particular case, we also carried out thermal cycloaddition reactions of each individual azide/alkyne combination and determined the product retention times by LCMS. This confirmed our initial determination that only one triazole was formed with an increased rate in the presence of the biological target, thereby illustrating that the enzyme was able to sample an array of potential inhibitor fragments and select only one productive combination, the one leading to the inhibitor 3.