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Molecular basis of SARS-CoV-2 infection and rational design of potential antiviral agents: Modeling and simulation approaches

2020

International audience; The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of k…

In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors

2020

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcu…

2020

Hsp70 proteins and their Hsp40 co-chaperones are essential components of cellular chaperone networks in both prokaryotes and eukaryotes. Here, we performed a genetic analysis to define the protein domains required for the key functions of the major Hsp40/DnaJ protein Sll0897 of the cyanobacterium Synechocystis sp. PCC6803. The expression of the N-terminally located J- and G/F-domains is essential and sufficient for the proteins' fundamental in vivo functions, whereas the presence of the full-length protein, containing the C-terminal substrate-binding domains, is crucial under stress conditions.

Cyclins B1, T1, and H differ in their molecular mode of interaction with cytomegalovirus protein kinase pUL97

2019

Human cytomegalovirus (HCMV) is a common β-herpesvirus causing life-long latent infections. HCMV replication interferes with cell cycle regulation in host cells because the HCMV-encoded cyclin-dependent kinase (CDK) ortholog pUL97 extensively phosphorylates the checkpoint regulator retinoblastoma protein. pUL97 also interacts with cyclins B1, T1, and H, and recent findings have strongly suggested that these interactions influence pUL97 substrate recognition. Interestingly, here we detected profound mechanistic differences among these pUL97-cyclin interactions. Our study revealed the following. (i) pUL97 interacts with cyclins B1 and H in a manner dependent on pUL97 activity and HCMV-specifi…

Transmembrane signaling and cytoplasmic signal conversion by dimeric transmembrane helix 2 and a linker domain of the DcuS sensor kinase

2020

Transmembrane (TM) signaling is a key process of membrane-bound sensor kinases. The C4-dicarboxylate (fumarate) responsive sensor kinase DcuS of Escherichia coli is anchored by TM helices TM1 and TM2 in the membrane. Signal transmission across the membrane relies on the piston-type movement of the periplasmic part of TM2. To define the role of TM2 in TM signaling, we use oxidative Cys cross-linking to demonstrate that TM2 extends over the full distance of the membrane and forms a stable TM homodimer in both the inactive and fumarate-activated state of DcuS. An S186xxxGxxxG194 motif is required for the stability and function of the TM2 homodimer. The TM2 helix further extends on the periplas…

Generation and Coherent Control of Pulsed Quantum Frequency Combs

2018

We present a method for the generation and coherent manipulation of pulsed quantum frequency combs. Until now, methods of preparing high-dimensional states on-chip in a practical way have remained elusive due to the increasing complexity of the quantum circuitry needed to prepare and process such states. Here, we outline how high-dimensional, frequency-bin entangled, two-photon states can be generated at a stable, high generation rate by using a nested-cavity, actively mode-locked excitation of a nonlinear micro-cavity. This technique is used to produce pulsed quantum frequency combs. Moreover, we present how the quantum states can be coherently manipulated using standard telecommunications…

Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators.

2016

Abstract The dopamine-amino acid conjugate DA-Phen was firstly designed to obtain a useful prodrug for the therapy of Parkinson's disease, but experimental evidence shows that it effectively interacts with D1 dopamine receptors (D1DRs), leading to an enhancement in cognitive flexibility and to the development of adaptive strategies in aversive mazes, together with a decrease in despair-like behavior. In this paper, homology modelling, molecular dynamics, and site mapping of D1 receptor were carried out with the aim of further performing docking studies on other dopamine conjugates compared with D1 agonists, in the attempt to identify new compounds with potential dopaminergic activity. Two n…

The therapeutic potential of inorganic polyphosphate: A versatile physiological polymer to control coronavirus disease (COVID-19).

2021

Rationale: The pandemic caused by the novel coronavirus SARS-CoV-2 is advancing rapidly. In particular, the number of severe courses of the disease is still dramatically high. An efficient drug therapy that helps to improve significantly the fatal combination of damages in the airway epithelia, in the extensive pulmonary microvascularization and finally multiorgan failure, is missing. The physiological, inorganic polymer, polyphosphate (polyP) is a molecule which could prevent the initial phase of the virus life cycle, the attachment of the virus to the target cells, and improve the epithelial integrity as well as the mucus barrier. Results: Surprisingly, polyP matches perfectly with the ca…

A Novel Open and Infectious Form of Echovirus 1.

2016

ABSTRACT One of the hallmarks of enterovirus genome delivery is the formation of an uncoating intermediate particle. Based on previous studies of mostly heated picornavirus particles, intermediate particles were shown to have externalized the innermost capsid protein (VP4) and exposed the N terminus of VP1 and to have reduced infectivity. Here, in addition to the native and intact particle type, we have identified another type of infectious echovirus 1 (E1) particle population during infection. Our results show that E1 is slightly altered during entry, which leads to the broadening of the major virion peak in the sucrose gradient. In contrast, CsCl gradient separation revealed that in addit…

Mixed topological semimetals driven by orbital complexity in two-dimensional ferromagnets

2018

The concepts of Weyl fermions and topological semimetals emerging in three-dimensional momentum space are extensively explored owing to the vast variety of exotic properties that they give rise to. On the other hand, very little is known about semimetallic states emerging in two-dimensional magnetic materials, which present the foundation for both present and future information technology. Here, we demonstrate that including the magnetization direction into the topological analysis allows for a natural classification of topological semimetallic states that manifest in two-dimensional ferromagnets as a result of the interplay between spin-orbit and exchange interactions. We explore the emerg…