Summary for 9C9V
| Entry DOI | 10.2210/pdb9c9v/pdb |
| Descriptor | Capsid protein, N'-(3-chloro-4-fluorophenyl)-N-(2-methylpropyl)-N-[(1R)-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl]urea (2 entities in total) |
| Functional Keywords | hbv capsid, assembly modulators, viral protein |
| Biological source | Hepatitis B virus |
| Total number of polymer chains | 6 |
| Total formula weight | 115838.39 |
| Authors | Olland, A.M.,Suto, R.K.,Fontano, E.,Colussi, T. (deposition date: 2024-06-16, release date: 2024-09-25, Last modification date: 2024-11-13) |
| Primary citation | Cole, A.G.,Kultgen, S.G.,Mani, N.,Fan, K.Y.,Ardzinski, A.,Stever, K.,Dorsey, B.D.,Mesaros, E.F.,Thi, E.P.,Graves, I.,Tang, S.,Harasym, T.O.,Lee, A.C.H.,Olland, A.,Suto, R.K.,Sofia, M.J. Rational Design, Synthesis, and Structure-Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836. J.Med.Chem., 67:16773-16795, 2024 Cited by PubMed Abstract: Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues. Key analogs demonstrated excellent primary potency, absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic properties, and efficacy in a mouse model of HBV. The optimized lead also displayed potent inhibition of capsid uncoating in HBV-infected HepG2 cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP) receptor, affecting the generation of HBsAg and cccDNA establishment. Based on these results, isoquinolinone derivative was advanced into clinical development. In Phase 1b trials, demonstrated >3 log reduction in serum HBV DNA, however, further development was discontinued due to the observation of incidental alanine aminotransferase (ALT) elevations. PubMed: 39231272DOI: 10.1021/acs.jmedchem.4c01568 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.63 Å) |
Structure validation
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