ABSTRACT
A myriad of microbes living together with the host constitutes the microbiota, and the microbiota exerts very diverse functions in the regulation of host physiology. Microbiota regulates cancer initiation, progression, metastasis, and responses to therapy. Here we review known pro-tumorigenic and anti-tumorigenic functions of microbiota, and mechanisms of how microbes can shape tumor microenvironment and affect cancer cells as well as activation and functionality of immune and stromal cells within the tumor. While some of these mechanisms are distal, often distinct members of microbiota travel with and establish colonization with the tumors in the distant organs. We further briefly describe recent findings regarding microbiota composition in metastasis and highlight important future directions and considerations for the manipulation of microbiota for cancer treatment.
Subject(s)
Microbiota , Neoplasms , Carcinogenesis , Humans , Tumor MicroenvironmentABSTRACT
The hepatitis C caused by the hepatitis C virus (HCV) is an acute and/or chronic liver disease ranging in severity from a mild brief ailment to a serious lifelong illness that affects up to 3% of the world population and imposes significant and increasing social, economic, and humanistic burden. Over the past decade, its treatment was revolutionized by the development and introduction into clinical practice of the direct acting antiviral (DAA) agents targeting the non-structural viral proteins NS3/4A, NS5A, and NS5B. However, the current treatment options still have important limitations, thus, the development of new classes of DAAs acting on different viral targets and having better pharmacological profile is highly desirable. The hepatitis C virus p7 viroporin is a relatively small hydrophobic oligomeric viral ion channel that plays a critical role during virus assembly and maturation, making it an attractive and validated target for the development of the cage compound-based inhibitors. Using the homology modeling, molecular dynamics, and molecular docking techniques, we have built a representative set of models of the hepatitis C virus p7 ion channels (Gt1a, Gt1b, Gt1b_L20F, Gt2a, and Gt2b), analyzed the inhibitor binding sites, and identified a number of potential broad-spectrum inhibitor structures targeting them. For one promising compound, the binding to these targets was additionally confirmed and the binding modes and probable mechanisms of action were clarified by the molecular dynamics simulations. A number of compounds were synthesized, and the tests of their antiviral activity (using the BVDV model) and cytotoxicity demonstrate their potential therapeutic usefulness and encourage further more detailed studies. The proposed approach is also suitable for the design of broad-spectrum ligands interacting with other multiple labile targets including various viroporins.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Design , Hepacivirus/drug effects , Hepatitis C/drug therapy , Viral Proteins/antagonists & inhibitors , Amino Acid Sequence , Antiviral Agents/chemical synthesis , Hepacivirus/chemistry , Hepacivirus/metabolism , Hepatitis C/virology , Humans , Molecular Docking Simulation , Sequence Alignment , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Viral Proteins/chemistry , Viral Proteins/metabolismABSTRACT
The asymmetric unit of the title compound, C(14)H(13)O(2)PS(2), contains two crystallographically independent mol-ecules, which differ in the conformation of the 1,3,2-benzoxathia-phosphinine moieties (screw boat in the first mol-ecule and envelope in the second mol-ecule). In the crystal, neither classical nor non-classical hydrogen bonds are found. Weak inter-actions (about 2.9-3.0â Å) between the lone pair of the terminal S atoms with H atoms occur. This compound was further characterized by (1)H NMR and IR spectroscopy.