scholarly journals Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry

2015 ◽  
Vol 89 (17) ◽  
pp. 8701-8712 ◽  
Author(s):  
Bernardo A. Mainou ◽  
Alison W. Ashbrook ◽  
Everett Clinton Smith ◽  
Daniel C. Dorset ◽  
Mark R. Denison ◽  
...  
Keyword(s):  
Cell Surface ◽  
Small Molecule ◽  
Receptor Agonist ◽  
Serotonin Receptor ◽  
Cell Entry ◽  
Receptor Signaling ◽  
Double Stranded Rna ◽  
Reovirus Infection ◽  
Small Molecule Screen ◽  
Diverse Virus

ABSTRACTMammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5-NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5-NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5-NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection byin vitro-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development.IMPORTANCEIdentification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target.

Improving voiding efficiency in the diabetic rat by a 5-HT1A serotonin receptor agonist

2011 ◽  
Vol 31 (1) ◽  
pp. 168-173 ◽  
Author(s):  
Baojun Gu ◽  
Gang Wu ◽  
Jieming Si ◽  
Yuemin Xu ◽  
Karl-Erik Andersson
Keyword(s):  
Receptor Agonist ◽  
Serotonin Receptor ◽  
Diabetic Rat

scholarly journals Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3

Cell Reports ◽  
2018 ◽  
Vol 22 (8) ◽  
pp. 1945-1955 ◽  
Author(s):  
Karina N. Gonzalez Herrera ◽  
Elma Zaganjor ◽  
Yoshinori Ishikawa ◽  
Jessica B. Spinelli ◽  
Haejin Yoon ◽  
...  
Keyword(s):  
Small Molecule ◽  
De Novo ◽  
Nucleotide Synthesis ◽  
Small Molecule Screen

scholarly journals Small molecule screen for compounds that affect vascular development in the zebrafish retina

2009 ◽  
Vol 126 (5-6) ◽  
pp. 464-477 ◽  
Author(s):  
Satish S. Kitambi ◽  
Kyle J. McCulloch ◽  
Randall T. Peterson ◽  
Jarema J. Malicki
Keyword(s):  
Small Molecule ◽  
Vascular Development ◽  
Small Molecule Screen

scholarly journals A Personal History of Using Crystals and Crystallography to Understand Biology and Advanced Drug Discovery

Crystals ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 676
Author(s):  
Tom L. Blundell
Keyword(s):  
Growth Factors ◽  
Drug Discovery ◽  
Cell Surface ◽  
Small Molecule ◽  
Personal History ◽  
X Ray ◽  
Surface Receptors ◽  
The Past ◽  
Industry Collaboration ◽  
History Of

Over the past 60 years, the use of crystals to define structures of complexes using X-ray analysis has contributed to the discovery of new medicines in a very significant way. This has been in understanding not only small-molecule inhibitors of proteins, such as enzymes, but also protein or peptide hormones or growth factors that bind to cell surface receptors. Experimental structures from crystallography have also been exploited in software to allow prediction of structures of important targets based on knowledge of homologues. Crystals and crystallography continue to contribute to drug design and provide a successful example of academia–industry collaboration.

scholarly journals Regulatory Role of the Morbillivirus Attachment Protein Head-to-Stalk Linker Module in Membrane Fusion Triggering

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Michael Herren ◽  
Neeta Shrestha ◽  
Marianne Wyss ◽  
Andreas Zurbriggen ◽  
Philippe Plattet
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cell Surface ◽  
Membrane Fusion ◽  
Measles Virus ◽  
Cell Entry ◽  
Regulatory Role ◽  
Fusion Activity ◽  
Animal Pathogens

ABSTRACTMorbillivirus (e.g., measles virus [MeV] and canine distemper virus [CDV]) host cell entry is coordinated by two interacting envelope glycoproteins, namely, an attachment (H) protein and a fusion (F) protein. The ectodomain of H proteins consists of stalk, connector, and head domains that assemble into functional noncovalent dimer-of-dimers. The role of the C-terminal module of the H-stalk domain (termed linker) and the connector, although putatively able to assume flexible structures and allow receptor-induced structural rearrangements, remains largely unexplored. Here, we carried out a nonconservative mutagenesis scan analysis of the MeV and CDV H-linker/connector domains. Our data demonstrated that replacing isoleucine 146 in H-linker (H-I146) with any charged amino acids prevented virus-mediated membrane fusion activity, despite proper trafficking of the mutants to the cell surface and preserved binding efficiency to the SLAM/CD150 receptor. Nondenaturing electrophoresis revealed that these charged amino acid changes led to the formation of irregular covalent H tetramers rather than functional dimer-of-dimers formed when isoleucine or other hydrophobic amino acids were present at residue position 146. Remarkably, we next demonstrated that covalent H tetramerizationper sewas not the only mechanism preventing F activation. Indeed, the neutral glycine mutant (H-I146G), which exhibited strong covalent tetramerization propensity, maintained limited fusion promotion activity. Conversely, charged H-I146 mutants, which additionally carried alanine substitution of natural cysteines (H-C139A and H-C154A) and thus were unable to form covalently linked tetramers, were fusion activation defective. Our data suggest a dual regulatory role of the hydrophobic residue at position 146 of the morbillivirus head-to-stalk H-linker module: securing the assembly of productive dimer-of-dimers and contributing to receptor-induced F-triggering activity.IMPORTANCEMeV and CDV remain important human and animal pathogens. Development of antivirals may significantly support current global vaccination campaigns. Cell entry is orchestrated by two interacting glycoproteins (H and F). The current hypothesis postulates that tetrameric H ectodomains (composed of stalk, connector, and head domains) undergo receptor-induced rearrangements to productively trigger F; these conformational changes may be regulated by the H-stalk C-terminal module (linker) and the following connector domain. Mutagenesis scan analysis of both microdomains revealed that replacing amino acid 146 in the H-linker region with nonhydrophobic residues produced covalent H tetramers which were compromised in triggering membrane fusion activity. However, these mutant proteins retained their ability to traffic to the cell surface and to bind to the virus receptor. These data suggest that the morbillivirus linker module contributes to the folding of functional pre-F-triggering H tetramers. Furthermore, such structures might be critical to convert receptor engagement into F activation.

Sign in / Sign up

Export Citation Format

Share Document