2. Academic Validation
  3. Optimization of potent, broad-spectrum, and specific anti-influenza compounds targeting RNA polymerase PA-PB1 heterodimerization

Optimization of potent, broad-spectrum, and specific anti-influenza compounds targeting RNA polymerase PA-PB1 heterodimerization

  • Eur J Med Chem. 2024 Aug 3:277:116737. doi: 10.1016/j.ejmech.2024.116737.
Anna Bonomini 1,  Tommaso Felicetti 2,  Martina Pacetti 2,  Chiara Bertagnin 1,  Alice Coletti 2,  Federica Giammarino 3,  Marta De Angelis 4,  Federica Poggialini 5,  Antonio Macchiarulo 2,  Stefano Sabatini 2,  Beatrice Mercorelli 1,  Lucia Nencioni 4,  Ilaria Vicenti 3,  Elena Dreassi 5,  Violetta Cecchetti 2,  Oriana Tabarrini 2,  Arianna Loregian 6,  Serena Massari 7
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, University of Padua, 35121, Padua, Italy.
  • 2 Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy.
  • 3 Department of Medical Biotechnologies, University of Siena, 53100, Siena, Italy.
  • 4 Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185, Rome, Italy.
  • 5 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100, Siena, Italy.
  • 6 Department of Molecular Medicine, University of Padua, 35121, Padua, Italy. Electronic address: arianna.loregian@unipd.it.
  • 7 Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy. Electronic address: serena.massari@unipg.it.
PMID: 39153334 DOI: 10.1016/j.ejmech.2024.116737
Abstract

Influenza viruses (IV) are single-stranded RNA viruses with a negative-sense genome and have the potential to cause pandemics. While vaccines exist for influenza, their protection is only partial. Additionally, there is only a limited number of approved anti-IV drugs, which are associated to emergence of drug resistance. To address these issues, for years we have focused on the development of small-molecules that can interfere with the heterodimerization of PA and PB1 subunits of the IV RNA-dependent RNA polymerase (RdRP). In this study, starting from a cycloheptathiophene-3-carboxamide compound that we recently identified, we performed iterative cycles of medicinal chemistry optimization that led to the identification of compounds 43 and 45 with activity in the nanomolar range against circulating A and B strains of IV. Mechanistic studies demonstrated the ability of 43 and 45 to interfere with viral RdRP activity by disrupting PA-PB1 subunits heterodimerization and to bind to the PA C-terminal domain through biophysical assays. Most important, ADME studies of 45 also showed an improvement in the pharmacokinetic profile with respect to the starting hit.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z