| Structural highlights
Function
[POLG_HRV2] 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. The capsid interacts with human VLDLR to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin-mediated endocytosis. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.[1] [2] VP0 precursor is a component of immature procapsids (By similarity).[3] [4] 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.[5] [6] Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).[7] [8] Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).[9] [10] Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).[11] [12] 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).[13] [14] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[15] [16]
Publication Abstract from PubMed
Human rhinovirus (HRV) is a primary cause of common cold and is linked to exacerbation of underlying respiratory diseases such as asthma and COPD. HRV 3C protease, which is responsible for cleavage of viral polyprotein in to proteins essential for viral life-cycle, represents an important target. We have designed proline- and azetidine-based analogues of Rupintrivir that target the P2 pocket of the binding site. Potency optimization, aided with X-ray crystallography and quantum mechanical calculations, led to compounds with activity against a broad spectrum of HRV serotypes. Altogether, these compounds represent alternative starting points to identify promising leads in our continual efforts to treat HRV infections.
Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease.,Kawatkar SP, Gagnon M, Hoesch V, Tiong-Yip C, Johnson K, Ek M, Nilsson E, Lister T, Olsson L, Patel J, Yu Q Bioorg Med Chem Lett. 2016 Jul 15;26(14):3248-52. doi:, 10.1016/j.bmcl.2016.05.066. Epub 2016 May 24. PMID:27265257[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Hewat EA, Neumann E, Blaas D. The concerted conformational changes during human rhinovirus 2 uncoating. Mol Cell. 2002 Aug;10(2):317-26. PMID:12191477
- ↑ Kawatkar SP, Gagnon M, Hoesch V, Tiong-Yip C, Johnson K, Ek M, Nilsson E, Lister T, Olsson L, Patel J, Yu Q. Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease. Bioorg Med Chem Lett. 2016 Jul 15;26(14):3248-52. doi:, 10.1016/j.bmcl.2016.05.066. Epub 2016 May 24. PMID:27265257 doi:http://dx.doi.org/10.1016/j.bmcl.2016.05.066
|
