scholarly journals HIV Protease: Historical Perspective and Current Research

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 839
Author(s):  
Irene T. Weber ◽  
Yuan-Fang Wang ◽  
Robert W. Harrison
Keyword(s):  
Molecular Mechanisms ◽  
Subsequent Development ◽  
Historical Background ◽  
Hiv Protease ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Evolution Of Resistance ◽  
Retroviral Proteases ◽  
And Function ◽  
Retroviral Protease

The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.

scholarly journals Targeting the bacterial SOS response for new antimicrobial agents: drug targets, molecular mechanisms and inhibitors

2021 ◽  
Author(s):  
Thomas Lanyon-Hogg
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Structure And Function ◽  
Drug Resistant ◽  
Target Validation ◽  
Sos Pathway ◽  
And Function

Antimicrobial resistance is a pressing threat to global health, with multidrug-resistant pathogens becoming increasingly prevalent. The bacterial SOS pathway functions in response to DNA damage that occurs during infection, initiating several pro-survival and resistance mechanisms, such as DNA repair and hypermutation. This makes SOS pathway components potential targets that may combat drug-resistant pathogens and decrease resistance emergence. This review discusses the mechanism of the SOS pathway; the structure and function of potential targets AddAB, RecBCD, RecA and LexA; and efforts to develop selective small-molecule inhibitors of these proteins. These inhibitors may serve as valuable tools for target validation and provide the foundations for desperately needed novel antibacterial therapeutics.

scholarly journals Molecular and Enzymatic Characterization of the Porcine Endogenous Retrovirus Protease

2002 ◽  
Vol 76 (15) ◽  
pp. 7913-7917 ◽  
Author(s):  
Jürgen H. Blusch ◽  
Sigrid Seelmeir ◽  
Klaus von der Helm
Keyword(s):  
High Specificity ◽  
Endogenous Retrovirus ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Amino Acid Residues ◽  
Porcine Endogenous Retrovirus ◽  
Immunodeficiency Virus ◽  
Retroviral Proteases

ABSTRACT The protease of the porcine endogenous retrovirus (PERV) subtypes A/B and C was recombinantly expressed in Escherichia coli as proteolytically active enzyme and characterized. The PERV Gag precursor was also recombinantly produced and used as the substrate in an in vitro enzyme assay in parallel with synthetic nonapeptide substrates designed according to cleavage site sequences identified in the PERV Gag precursor. The proteases of all PERV subtypes consist of 127 amino acid residues with an M r of 14,000 as revealed by determining the protease N and C termini. The PERV proteases have a high specificity for PERV substrates and do not cleave human immunodeficiency virus (HIV)-specific substrates, nor are they inhibited by specific HIV protease inhibitors. Among the known retroviral proteases, the PERV proteases resemble most closely the protease of the murine leukemia retrovirus.

IL-10-592 A/C Gene Polymorphism and Cytokine Levels are Associated with Susceptibility to Drug Resistance in Tuberculosis

2020 ◽  
Vol 8 (3) ◽  
pp. 103-112
Author(s):  
Atefeh SADEGHI SHERMEH ◽  
Majid KHOSHMIRSAFA ◽  
Ali-Akbar DELBANDI ◽  
Payam TABARSI ◽  
Esmaeil MORTAZ ◽  
...  
Keyword(s):  
Serum Levels ◽  
World Health ◽  
Control Group ◽  
Drug Resistant ◽  
Nucleotide Polymorphisms ◽  
Genotype Frequencies ◽  
Cytokine Levels ◽  
Ifn Γ ◽  
Health Organization ◽  
And Function

Introduction: Tuberculosis (TB) and especially resistant forms of it have a substantial economic burden on the community health system for diagnosis and treatment each year. Thus, investigation of this field is a priority for the world health organization (WHO). Cytokines play important roles in the relationship between the immune system and tuberculosis. Genetic variations especially single nucleotide polymorphisms (SNPs) impact cytokine levels and function against TB. Material and Methods: In this research SNPs in IFN-γ (+874 T/A) and IL-10 (-592 A/C) genes, and the effects of these SNPs on cytokine levels in a total of 87 tuberculosis patients and 100 healthy controls (HCs) were studied. TB patients divided into two groups: 1) 67 drug-sensitive (DS-TB) and 2) 20 drug-resistant (DR-TB) according to drug sensitivity test using polymerase chain reaction (PCR). For the genotyping of two SNPs, the PCR-based method was used and IFN-γ and IL-10 levels were measured by ELISA in pulmonary tuberculosis (PTB) and control group. Results: In -592A/C SNP, only two genotypes (AA, AC) were observed and both genotypes showed statistically significant differences between DR-TB and HCs (p=0.011). IL-10 serum levels in PTB patients were higher than HCs (p=0.02). The serum levels of IFN-γ were significantly higher in DS-TB patients than that of the other two groups (p<0.001); however, no significant differences were observed for allele and genotype frequencies in IFN-γ +874. Conclusions: Our results suggest that the SNP at -592 position of IL-10 gene may be associated with the susceptibility to DR-TB. However, further investigation is necessary. Keywords: Polymorphism, IFN-γ, IL-10, tuberculosis, drug-resistant tuberculosis

A Mucin-Specific Protease Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

2018 ◽  
Author(s):  
Stacy A. Malaker ◽  
Kayvon Pedram ◽  
Michael J. Ferracane ◽  
Elliot C. Woods ◽  
Jessica Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
High Resolution Mass Spectrometry ◽  
Human Cancer ◽  
Glycosylation Sites ◽  
Bacterial Protease ◽  
Specific Protease ◽  
To Come ◽  
And Function

<div> <div> <div> <p>Mucins are a class of highly O-glycosylated proteins that are ubiquitously expressed on cellular surfaces and are important for human health, especially in the context of carcinomas. However, the molecular mechanisms by which aberrant mucin structures lead to tumor progression and immune evasion have been slow to come to light, in part because methods for selective mucin degradation are lacking. Here we employ high resolution mass spectrometry, polymer synthesis, and computational peptide docking to demonstrate that a bacterial protease, called StcE, cleaves mucin domains by recognizing a discrete peptide-, glycan-, and secondary structure- based motif. We exploited StcE’s unique properties to map glycosylation sites and structures of purified and recombinant human mucins by mass spectrometry. As well, we found that StcE will digest cancer-associated mucins from cultured cells and from ovarian cancer patient-derived ascites fluid. Finally, using StcE we discovered that Siglec-7, a glyco-immune checkpoint receptor, specifically binds sialomucins as biological ligands, whereas the related Siglec-9 receptor does not. Mucin-specific proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of glycoprotein structure and function and for deorphanizing mucin-binding receptors. </p> </div> </div> </div>

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals Emerging Data on the Diversity of Molecular Mechanisms Involving C/D snoRNAs

2021 ◽  
Vol 7 (2) ◽  
pp. 30
Author(s):  
Laeya Baldini ◽  
Bruno Charpentier ◽  
Stéphane Labialle
Keyword(s):  
Ribosomal Rna ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Accurate Description ◽  
Small Nucleolar Rnas ◽  
Age Of Maturity ◽  
Non Coding Rnas ◽  
And Function ◽  
Nucleolar Rnas

Box C/D small nucleolar RNAs (C/D snoRNAs) represent an ancient family of small non-coding RNAs that are classically viewed as housekeeping guides for the 2′-O-methylation of ribosomal RNA in Archaea and Eukaryotes. However, an extensive set of studies now argues that they are involved in mechanisms that go well beyond this function. Here, we present these pieces of evidence in light of the current comprehension of the molecular mechanisms that control C/D snoRNA expression and function. From this inventory emerges that an accurate description of these activities at a molecular level is required to let the snoRNA field enter in a second age of maturity.

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