TY - JOUR
T1 - Inhibition of Influenza Virus Replication by Oseltamivir Derivatives
AU - Chan, Renee W.Y.
AU - Tao, Kin P.
AU - Ye, Jiqing
AU - Lui, Kevin K.Y.
AU - Yang, Xiao
AU - Ma, Cong
AU - Chan, Paul K.S.
N1 - Funding Information:
Funding: This research was funded by Health and Medical Research Fund-Commissioned Programme for Influenza Research, Ref: INF-CUHK-2 to R.W.Y.C., by the Research Fund Secretariat of the Food and Health Bureau, The Government of the Hong Kong Special Admirative Region.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/11
Y1 - 2022/2/11
N2 - Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concen-tration (IC50). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200.
AB - Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concen-tration (IC50). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200.
KW - Influenza antiviral
KW - Influenza virus
KW - Oseltamivir derivatives
KW - Oseltamivir-resistant
UR - http://www.scopus.com/inward/record.url?scp=85124836425&partnerID=8YFLogxK
U2 - 10.3390/pathogens11020237
DO - 10.3390/pathogens11020237
M3 - Journal article
AN - SCOPUS:85124836425
SN - 2076-0817
VL - 11
JO - Pathogens
JF - Pathogens
IS - 2
M1 - 237
ER -
