Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus.
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-imidazoline (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 IC(50) as low as 0.92 +/- 0.11 microM against AM2, more than an order of magnitude more potent than amantadine (IC(50) = 16 microM). (15)N and (13)C 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.
Wang
Jun
J
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6059, USA.
Cady
Sarah D
SD
Balannik
Victoria
V
Pinto
Lawrence H
LH
DeGrado
William F
WF
Hong
Mei
M
D000547:Amantadine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects*; D009865:Oocytes; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors*; D014981:Xenopus; D000086082:Viroporin Proteins
D000547:Amantadine; D000998:Antiviral Agents; D007093:Imidazoles; D010880:Piperidines; D013141:Spiro Compounds; D014763:Viral Matrix Proteins; C100337:2-(3-azaspiro(5,5)undecanol)-2-imidazoline; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C032727:piperidine