TY - JOUR
T1 - Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses
AU - Tzitzoglaki, Christina
AU - Hoffmann, Anja
AU - Turcu, Andreea L.
AU - Schmerer, Patrick
AU - Ma, Chunlong
AU - Laros, George
AU - Liolios, Christos
AU - José, Brea
AU - Wang, Jun
AU - Vázquez, Santiago
AU - Schmidtke, Michaela
AU - Kolocouris, Antonios
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/12
Y1 - 2022/12
N2 - Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine drugs inhibit influenza A M2 wild-type (WT; bearing in the protein M2 proton channel serine at position-31) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to these drugs influenza A viruses bearing the S31N mutant in the M2 proton channel can be inhibited by amantadine – aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31N channel-mediated proton current. However, the M2 amantadine/rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 channel pore pose an additional concern for public health. Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses. We identified 16 compounds that inhibited in vitro two influenza A viruses with M2 WT or L26F channels. Additionally, compounds 21 or 32 or 33, which are conjugates of the rimantadine variant with CMe2 (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound 21 inhibited also in vitro the M2 G34E virus and compound 32 inhibited also in vitro the M2 A30T virus. Also, using electrophysiology, we showed that compound 21 was an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocked efficiently the M2 WT channel and compound 33 blocked the M2 WT, L26F and V27A channels. The drug metabolism and pharmacokinetics studies showed that these compounds need further optimization.
AB - Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine drugs inhibit influenza A M2 wild-type (WT; bearing in the protein M2 proton channel serine at position-31) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to these drugs influenza A viruses bearing the S31N mutant in the M2 proton channel can be inhibited by amantadine – aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31N channel-mediated proton current. However, the M2 amantadine/rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 channel pore pose an additional concern for public health. Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses. We identified 16 compounds that inhibited in vitro two influenza A viruses with M2 WT or L26F channels. Additionally, compounds 21 or 32 or 33, which are conjugates of the rimantadine variant with CMe2 (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound 21 inhibited also in vitro the M2 G34E virus and compound 32 inhibited also in vitro the M2 A30T virus. Also, using electrophysiology, we showed that compound 21 was an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocked efficiently the M2 WT channel and compound 33 blocked the M2 WT, L26F and V27A channels. The drug metabolism and pharmacokinetics studies showed that these compounds need further optimization.
KW - A30T
KW - Amantadine - aryl conjugate
KW - CPE
KW - Electrophysiology
KW - G34E
KW - In vitro antiviral activity
KW - Influenza A M2 protein
KW - L26F
KW - S31N
KW - Synthesis
KW - TEVC
KW - V27A
KW - WSN/33
UR - http://www.scopus.com/inward/record.url?scp=85148422685&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148422685&partnerID=8YFLogxK
U2 - 10.1016/j.ejmcr.2022.100083
DO - 10.1016/j.ejmcr.2022.100083
M3 - Article
AN - SCOPUS:85148422685
SN - 2772-4174
VL - 6
JO - European Journal of Medicinal Chemistry Reports
JF - European Journal of Medicinal Chemistry Reports
M1 - 100083
ER -