Inhibition of mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives

Jing Ping Lu, Xiu Hua Yuan, Hai Yuan, Wen Long Wang, Baojie Wan, Scott G. Franzblau, Qizhuang Ye

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target for the development of novel antitubercular agents. Natural bengamides potently inhibit the proliferation of mammalian cells by targeting MetAP enzymes, and the X-ray crystal structure of human type2 MetAP in complex with a bengamide derivative reveals the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1a and MtMetAP1c in different metalloforms, inhibition of M.tuberculosis growth in replicating and non-replicating states, and inhibition of human K562 cell growth. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M.tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity. Better fitness: A synthetic bengamide derivative occupies the active site of M.tuberculosis methionine aminopeptidase (MetAP), exploring the interactions around the binding pocket. Several analogues of the natural bengamides were designed and synthesized as novel antitubercular agents.

Original languageEnglish
Pages (from-to)1041-1048
Number of pages8
JournalChemMedChem
Volume6
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Aminopeptidases
Mycobacterium tuberculosis
Methionine
Antitubercular Agents
Derivatives
Tuberculosis
Catalytic Domain
Growth
Crystal structure
K562 Cells
Cell growth
Cell Proliferation
X-Rays
Bacteria
Cells
Enzymes
X rays
Processing
Proteins

Keywords

  • Antibiotics
  • Drug discovery
  • Hydrolases
  • Inhibitors
  • Metalloenzymes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Lu, J. P., Yuan, X. H., Yuan, H., Wang, W. L., Wan, B., Franzblau, S. G., & Ye, Q. (2011). Inhibition of mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives. ChemMedChem, 6(6), 1041-1048. https://doi.org/10.1002/cmdc.201100003

Inhibition of mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives. / Lu, Jing Ping; Yuan, Xiu Hua; Yuan, Hai; Wang, Wen Long; Wan, Baojie; Franzblau, Scott G.; Ye, Qizhuang.

In: ChemMedChem, Vol. 6, No. 6, 06.2011, p. 1041-1048.

Research output: Contribution to journalArticle

Lu, JP, Yuan, XH, Yuan, H, Wang, WL, Wan, B, Franzblau, SG & Ye, Q 2011, 'Inhibition of mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives', ChemMedChem, vol. 6, no. 6, pp. 1041-1048. https://doi.org/10.1002/cmdc.201100003
Lu, Jing Ping ; Yuan, Xiu Hua ; Yuan, Hai ; Wang, Wen Long ; Wan, Baojie ; Franzblau, Scott G. ; Ye, Qizhuang. / Inhibition of mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives. In: ChemMedChem. 2011 ; Vol. 6, No. 6. pp. 1041-1048.
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