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Peer-reviewedCC BYOrganic & biomolecular chemistry

4-Diketopyrrole-2-carboxamide derivatives affecting HBV capsid assembly: structure-activity relationship around the GLP-26 scaffold.

  • Zhe Chen1
  • Shaoman Zhou1
  • Peng Liu1
  • John Wiseman1
  • Longhu Zhou1
  • Chia-Han Vanessa Fan1
  • Heather B Bowers1
  • Mohammad Salman1
  • Kiran Verma1
  • Danielle R Monroe1
  • Jessica Downs-Bowen1
  • Dharmeshkumar Patel1
3 more authors
  • Leda Bassit1
  • Raymond F Schinazi1
  • Franck Amblard1
  1. 1Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. [email protected].
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Abstract

Chronic hepatitis B virus (HBV) infection remains a major global health burden with limited curative options. Capsid assembly modulators (CAMs) have emerged as a promising antiviral strategy by disrupting nucleocapsid formation and suppressing cccDNA amplification. In this study, we discuss the structure-activity relationship (SAR) around the 4-diketopyrrole-2-carboxamide scaffold of GLP-26, focusing on modifying the aniline moiety and the oxoacetamide region, and introducing alternative acetamide groups. Compounds were synthesized through efficient coupling strategies, including microwave-assisted amidation, and several analogs exhibited potent inhibition of HBV DNA replication in HepAD38 cells, with EC₅₀ values in the low nanomolar range and minimal cytotoxicity. This work broadens the chemical space surrounding GLP-26 and provides a valuable roadmap for designing new scaffolds for next-generation HBV CAMs.

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Cite

BibTeXRIS
BibTeX
@article{chen20264diketopyrrole2carboxamide,
  title = {{4-Diketopyrrole-2-carboxamide derivatives affecting HBV capsid assembly: structure-activity relationship around the GLP-26 scaffold.}},
  author = {Zhe Chen and Shaoman Zhou and Peng Liu and John Wiseman and Longhu Zhou and Chia-Han Vanessa Fan and Heather B Bowers and Mohammad Salman and Kiran Verma and Danielle R Monroe and Jessica Downs-Bowen and Dharmeshkumar Patel and Leda Bassit and Raymond F Schinazi and Franck Amblard},
  journal = {Organic \& biomolecular chemistry},
  year = {2026},
  month = oct,
  doi = {10.1039/d6ob00943c},
  url = {https://europepmc.org/article/MED/42851025},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - 4-Diketopyrrole-2-carboxamide derivatives affecting HBV capsid assembly: structure-activity relationship around the GLP-26 scaffold.
AU  - Zhe Chen
AU  - Shaoman Zhou
AU  - Peng Liu
AU  - John Wiseman
AU  - Longhu Zhou
AU  - Chia-Han Vanessa Fan
AU  - Heather B Bowers
AU  - Mohammad Salman
AU  - Kiran Verma
AU  - Danielle R Monroe
AU  - Jessica Downs-Bowen
AU  - Dharmeshkumar Patel
AU  - Leda Bassit
AU  - Raymond F Schinazi
AU  - Franck Amblard
PY  - 2026
DA  - 2026/10/21
JO  - Organic & biomolecular chemistry
DO  - 10.1039/d6ob00943c
UR  - https://europepmc.org/article/MED/42851025
AB  - Chronic hepatitis B virus (HBV) infection remains a major global health burden with limited curative options. Capsid assembly modulators (CAMs) have emerged as a promising antiviral strategy by disrupting nucleocapsid formation and suppressing cccDNA amplification. In this study, we discuss the structure-activity relationship (SAR) around the 4-diketopyrrole-2-carboxamide scaffold of GLP-26, focusing on modifying the aniline moiety and the oxoacetamide region, and introducing alternative acetamide groups. Compounds were synthesized through efficient coupling strategies, including microwave-assisted amidation, and several analogs exhibited potent inhibition of HBV DNA replication in HepAD38 cells, with EC₅₀ values in the low nanomolar range and minimal cytotoxicity. This work broadens the chemical space surrounding GLP-26 and provides a valuable roadmap for designing new scaffolds for next-generation HBV CAMs.
SN  - 1477-0520
SN  - 1477-0539
ER  -