9fcz
Coxsackievirus A9 bound with compound 17 (CL301)
Structural highlights
FunctionPOLG_CXA9 Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes (By similarity). Capsid proteins interact with host alpha-V/beta-6 integrin heterodimer to provide virion attachment target cell. VP0 precursor is a component of immature procapsids (By similarity). Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription (By similarity). Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity). Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity). Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity). Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity). RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity). Publication Abstract from PubMedEnterovirus infections are common in humans, yet there are no approved antiviral treatments. In this study we concentrated on inhibition of one of the Enterovirus B (EV-B), namely Coxsackievirus A9 (CVA9), using a combination of medicinal chemistry, virus inhibition assays, structure determination from cryogenic electron microscopy and molecular modeling, to determine the structure activity relationships for a promising class of novel N-phenylbenzylamines. Of the new 29 compounds synthesized, 10 had half maximal effective concentration (EC(50)) values between 0.64-10.46 muM, and of these, 7 had 50% cytotoxicity concentration (CC(50)) values higher than 200 muM. In addition, this new series of compounds showed promising physicochemical properties and act through capsid stabilization, preventing capsid expansion and subsequent release of the genome. SAR Analysis of Novel Coxsackie virus A9 Capsid Binders.,Tammaro C, Plavec Z, Myllymaki L, Mitchell C, Consalvi S, Biava M, Ciogli A, Domanska A, Leppilampi V, Buckner C, Manetto S, Scio P, Coluccia A, Laajala M, Dondio GM, Bigogno C, Marjomaki V, Butcher SJ, Poce G J Med Chem. 2024 Sep 18. doi: 10.1021/acs.jmedchem.4c00701. PMID:39292620[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
