ORCID Profile
0000-0002-6529-9256
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Publisher: Springer Science and Business Media LLC
Date: 28-03-2023
DOI: 10.1038/S41467-023-37254-W
Abstract: Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we design a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibits PLpro with k inact /K I = 9,600 M −1 s −1 , achieves sub-μM EC 50 values against three SARS-CoV-2 variants in mammalian cell lines, and does not inhibit a panel of human deubiquitinases (DUBs) at μM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validates our design strategy and establishes the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.
Publisher: Society of Exploration Geophysicists
Date: 05-2020
Abstract: Seismic waves may exhibit significant dispersion and attenuation in reservoir rocks due to pore-scale fluid flow. Fluid flow at the microscopic scale is referred to as squirt flow and occurs in very compliant pores, such as grain contacts or microcracks, that are connected to other stiffer pores. We have performed 3D numerical simulations of squirt flow using a finite-element approach. Our 3D numerical models consist of a pore space embedded into a solid grain material. The pore space is represented by a flat cylinder (a compliant crack) whose edge is connected with a torus (a stiff pore). Grains are described as a linear isotropic elastic material, whereas the fluid phase is described by the quasistatic linearized compressible Navier-Stokes momentum equation. We obtain the frequency-dependent effective stiffness of a porous medium and calculate dispersion and attenuation due to fluid flow from a compliant crack to a stiff pore. We compare our numerical results against a published analytical solution for squirt flow and analyze the effects of its assumptions. Previous interpretation of the squirt flow phenomenon based mainly on analytical solutions is verified, and some new physical effects are identified. The numerical and analytical solutions agree only for the simplest model in which the edge of the crack is subjected to zero fluid pressure boundary condition while the stiff pore is absent. For the more realistic model that includes the stiff pore, significant discrepancies are observed. We identify two important aspects that need improvement in the analytical solution: the calculation of the frame stiffness moduli and the frequency dependence of attenuation and dispersion at intermediate frequencies.
No related grants have been discovered for Yury Alkhimenkov.