PF74 and Its Novel Derivatives Stabilize Hexameric Lattice of HIV-1 Mature-Like Particles
| Autor: | Richard Hrabal, Michaela Rumlová, Alžběta Dostálková, Filip Kaufman, Ivana Křížová, Tomáš Ruml, Kryštof Škach, Romana Hadravová, Martin Flegel |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Indoles Magnetic Resonance Spectroscopy Anti-HIV Agents medicine.medical_treatment viruses Molecular Conformation Pharmaceutical Science PF74 derivatives Chemistry Techniques Synthetic HIV-1 CA inhibitor Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound lcsh:Organic chemistry Drug Discovery medicine Humans Physical and Theoretical Chemistry 030304 developmental biology 0303 health sciences Protease Molecular Structure biology 030306 microbiology Virus Assembly Organic Chemistry Virion RNA disassembly Small molecule Recombinant Proteins In vitro Reverse transcriptase Capsid chemistry Chemistry (miscellaneous) Drug Design HIV-1 Biophysics biology.protein Molecular Medicine Capsid Proteins uncoating Protein A DNA |
| Zdroj: | Molecules Volume 25 Issue 8 Molecules, Vol 25, Iss 1895, p 1895 (2020) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules25081895 |
| Popis: | A major structural retroviral protein, capsid protein (CA), is able to oligomerize into two different hexameric lattices, which makes this protein a key component for both the early and late stages of HIV-1 replication. During the late stage, the CA protein, as part of the Gag polyprotein precursor, facilitates protein&ndash protein interactions that lead to the assembly of immature particles. Following protease activation and Gag polyprotein processing, CA also drives the assembly of the mature viral core. In the early stage of infection, the role of the CA protein is distinct. It controls the disassembly of the mature CA hexameric lattice i.e., uncoating, which is critical for the reverse transcription of the single-stranded RNA genome into double stranded DNA. These properties make CA a very attractive target for small molecule functioning as inhibitors of HIV-1 particle assembly and/or disassembly. Of these, inhibitors containing the PF74 scaffold have been extensively studied. In this study, we reported a series of modifications of the PF74 molecule and its characterization through a combination of biochemical and structural approaches. Our data supported the hypothesis that PF74 stabilizes the mature HIV-1 CA hexameric lattice. We identified derivatives with a higher in vitro stabilization activity in comparison to the original PF74 molecule. |
| Databáze: | OpenAIRE |
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