Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus

Jun Wang, Sarah D. Cady, Victoria Balannik, Lawrence H. Pinto, William F. DeGrado, Mei Hong

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Amantadine has been used for decades as an inhibitor of the influenza A virus M2 protein (AM2) in the prophylaxis and treatment of influenza A infections, but its clinical use has been limited by its central nervous system (CNS) side effects as well as emerging drug-resistant strains of the virus. With the goal of searching for new classes of M2 inhibitors, a structure-activity relation study based on 2-[3-azaspiro(5,5)undecanol]-2-midazoline (BL-1743) was initiated. The first generation BL-1743 series of compounds has been synthesized and tested by two-electrode voltage-clamp (TEV) assays. The most active compound from this library, 3-azaspiro[5,5]undecane hydrochloride (9), showed an IC50 as low as 0.92 ± 0.11 μM against AM2, more than an order of magnitude more potent than amantadine (IC50 = 16 μM). 15N and 13C solid-state NMR was employed to determine the effect of compound 9 on the structure and dynamics of the transmembrane domain of AM2 (AM2-TM) in phospholipid bilayers. Compared to amantadine, spiro-piperidine 9 (1) induces a more homogeneous conformation of the peptide, (2) reduces the dynamic disorder of the G34-I35 backbone near the water-filled central cavity of the helical bundle, and (3) influences the dynamics and magnetic environment of more residues within the transmembrane helices. These data suggest that spiro-piperidine 9 binds more extensively with the AM2 channel, thus leading to stronger inhibitory potency.

Original languageEnglish (US)
Pages (from-to)8066-8076
Number of pages11
JournalJournal of the American Chemical Society
Volume131
Issue number23
DOIs
StatePublished - Jun 17 2009
Externally publishedYes

Fingerprint

Amantadine
Influenza A virus
Viruses
Protons
Modulation
Inhibitory Concentration 50
Phospholipids
Clamping devices
Neurology
Human Influenza
Peptides
Libraries
Conformations
Assays
Electrodes
Central Nervous System
Nuclear magnetic resonance
Proteins
Water
Electric potential

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. / Wang, Jun; Cady, Sarah D.; Balannik, Victoria; Pinto, Lawrence H.; DeGrado, William F.; Hong, Mei.

In: Journal of the American Chemical Society, Vol. 131, No. 23, 17.06.2009, p. 8066-8076.

Research output: Contribution to journalArticle

Wang, Jun ; Cady, Sarah D. ; Balannik, Victoria ; Pinto, Lawrence H. ; DeGrado, William F. ; Hong, Mei. / Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. In: Journal of the American Chemical Society. 2009 ; Vol. 131, No. 23. pp. 8066-8076.
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