TY - JOUR
T1 - Discovery of a small molecule inhibitor of human adenovirus capable of preventing escape from the endosome
AU - Xu, Jimin
AU - Berastegui-Cabrera, Judith
AU - Carretero-Ledesma, Marta
AU - Chen, Haiying
AU - Xue, Yu
AU - Wold, Eric A.
AU - Pachón, Jerónimo
AU - Zhou, Jia
AU - Sánchez-Céspedes, Javier
N1 - Funding Information:
Funding: This work was partially supported by the UTMB Technology Commercialization Program, the John D. Stobo, M. D. Distinguished Chair Endowment Fund (to JZ) and John Sealy Memorial Endowment Fund at UTMB, Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by the European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 20142020, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI15/00489) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018) Servicio Andaluz de Salud, Junta de Andalucía. E.A.W. is supported by the National Institutes of Health (NIH) National Research Service Award (NRSA) F31 DA04551. E.A.W. and J.Z.
Funding Information:
This work was partially supported by the UTMB Technology Commercialization Program, the John D. Stobo, M. D. Distinguished Chair Endowment Fund (to JZ) and John Sealy Memorial Endowment Fund at UTMB, Plan Nacional de I + D + i 2013?2016 and Instituto de Salud Carlos III, Subdirecci?n General de Redes y Centros de Investigaci?n Cooperativa, Ministerio de Econom?a, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by the European Development Regional Fund ?A way to achieve Europe?, Operative program Intelligent Growth 20142020, the Instituto de Salud Carlos III, Proyectos de Investigaci?n en Salud (PI15/00489) and Proyectos de Desarrollo Tecnol?gico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program ?Nicol?s Monardes? (C-0059-2018) Servicio Andaluz de Salud, Junta de Andaluc?a. E.A.W. is supported by the National Institutes of Health (NIH) National Research Service Award (NRSA) F31 DA04551. E.A.W. and J.Z. have no financial connections with the above European funding sources, and thus there is no conflict of interest to disclose.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicy-lamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.
AB - Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicy-lamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.
KW - Adenovirus
KW - Antiviral agent
KW - Entry inhibition
KW - Salicylamide derivatives
UR - http://www.scopus.com/inward/record.url?scp=85100469674&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100469674&partnerID=8YFLogxK
U2 - 10.3390/ijms22041617
DO - 10.3390/ijms22041617
M3 - Article
C2 - 33562748
AN - SCOPUS:85100469674
SN - 1661-6596
VL - 22
SP - 1
EP - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 4
M1 - 1617
ER -