Display options
Cite
Mac Sweeney A, Grosche P, Ellis D, et al. Discovery and structure-based optimization of adenain inhibitors. ACS Med Chem Lett. 2014;5(8):937-41doi: 10.1021/ml500224t.
Mac Sweeney, A., Grosche, P., Ellis, D., Combrink, K., Erbel, P., Hughes, N., Sirockin, F., Melkko, S., Bernardi, A., Ramage, P., Jarousse, N., & Altmann, E. (2014). Discovery and structure-based optimization of adenain inhibitors. ACS medicinal chemistry letters, 5(8), 937-41. https://doi.org/10.1021/ml500224t
Mac Sweeney, Aengus, et al. "Discovery and structure-based optimization of adenain inhibitors." ACS medicinal chemistry letters vol. 5,8 (2014): 937-41. doi: https://doi.org/10.1021/ml500224t
Mac Sweeney A, Grosche P, Ellis D, Combrink K, Erbel P, Hughes N, Sirockin F, Melkko S, Bernardi A, Ramage P, Jarousse N, Altmann E. Discovery and structure-based optimization of adenain inhibitors. ACS Med Chem Lett. 2014 Jun 20;5(8):937-41. doi: 10.1021/ml500224t. eCollection 2014 Aug 14. PMID: 25147618; PMCID: PMC4137446.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2014 Jun 20;5(8):937-41. doi: 10.1021/ml500224t. eCollection 2014 Aug 14.

Discovery and structure-based optimization of adenain inhibitors.

ACS medicinal chemistry letters

Aengus Mac Sweeney, Philipp Grosche, David Ellis, Keith Combrink, Paul Erbel, Nicola Hughes, Finton Sirockin, Samu Melkko, Anna Bernardi, Paul Ramage, Nadine Jarousse, Eva Altmann

Affiliations

  1. Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
  2. Novartis Institute for Biomedical Research , 6201 South Freeway, Fort Worth, Texas 76134-2099, United States.
  3. Novartis Institute for Biomedical Research , 4560 Horton Street, Emeryville, California 94608-2916, United States.

PMID: 25147618 PMCID: PMC4137446 DOI: 10.1021/ml500224t

Abstract

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Keywords: Adenoviral protease; adenoviral infection; inhibitor X-ray cocrystal structure; structure-based design

References

  1. J Comput Aided Mol Des. 2012 Aug;26(8):935-45 - PubMed
  2. Curr Opin Ophthalmol. 2011 Jul;22(4):290-3 - PubMed
  3. Expert Opin Drug Metab Toxicol. 2005 Aug;1(2):175-85 - PubMed
  4. J Biomol Screen. 2014 Jul;19(6):870-7 - PubMed
  5. Cell Mol Life Sci. 2003 Nov;60(11):2347-55 - PubMed
  6. Invest Ophthalmol Vis Sci. 2012 May 14;53(6):2804-11 - PubMed
  7. J Antimicrob Chemother. 2005 Apr;55(4):424-9 - PubMed
  8. Acta Microbiol Immunol Hung. 2003;50(1):95-101 - PubMed
  9. Curr Drug Metab. 2008 Nov;9(9):886-92 - PubMed
  10. FEBS Lett. 2013 Aug 2;587(15):2332-9 - PubMed
  11. J Virol. 1993 Jun;67(6):3507-14 - PubMed
  12. J Med Chem. 2010 Mar 25;53(6):2601-11 - PubMed
  13. Virus Res. 2002 Oct;89(1):41-52 - PubMed
  14. Rev Med Virol. 1998 Oct;8(4):213-222 - PubMed
  15. EMBO J. 1996 Apr 15;15(8):1766-77 - PubMed
  16. Biochemistry. 2001 Dec 4;40(48):14468-74 - PubMed
  17. Rev Med Virol. 2008 Nov-Dec;18(6):357-74 - PubMed
  18. ACS Comb Sci. 2013 May 13;15(5):217-28 - PubMed

Publication Types