Organic Chemistry By Dr. I. L. Finar. Vol. 2: Stereochemistry and the Chemistry of Natural Products. Pp. xi + 733. (London and New York: Longmans, Green and Co., Ltd., 1956.) 40s. net.

Advanced Organic Chemistry

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22306

Toll-like receptors and adaptor molecules in liver disease: update.

Hepatitis C virus (HCV) will continue to be a serious global health threat for many years to come because of the chronic nature of the infection, its high prevalence and the significant morbidity of the resulting disease. Recently, a small number of molecules have produced encouraging results in proof-of-concept clinical trials. At the same time, preclinical evidence is accumulating that development of resistance will eventually limit the efficacy of new drugs. Thus, combinations of multiple agents will be required to treat chronic HCV infection.

https://courses.washington.edu/conj504/readings/polyak_reading3.pdf

Challenges and successes in developing new therapies for hepatitis C

TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.

/pdf/tlr-activated-b-cells-suppress-t-cell-mediated-autoimmunity-2z7szdhh1o.pdf

TLR-Activated B Cells Suppress T Cell-Mediated Autoimmunity

Since first being described in the fruit fly Drosophila melanogaster, Toll-like receptors (TLRs) have proven to be of great interest to immunologists and investigators interested in the molecular basis to inflammation. They recognize pathogen-derived factors and also products of inflamed tissue, and trigger signaling pathways that lead to activation of transcription factors such as nuclear factor-κB and the interferon regulatory factors. These in turn lead to induction of immune and inflammatory genes, including such important cytokines as tumor necrosis factor-α and type I interferon. Much evidence points to a role for TLRs in immune and inflammatory diseases and increasingly in cancer. Examples include clear roles for TLR4 in sepsis, rheumatoid arthritis, ischemia/reperfusion injury, and allergy. TLR2 has been implicated in similar pathologic conditions and also in systemic lupus erythematosus (SLE) and tumor metastasis. TLR7 has also been shown to be important in SLE. TLR5 has been shown to be radioprotective. Recent advances in our understanding of signaling pathways activated by TLRs, structural insights into TLRs bound to their ligands and antagonists, and approaches to inhibit TLRs (including antibodies, peptides, and small molecules) are providing possiblemeans by which to interfere with TLRs clinically. Here we review these recent advances and speculate about whether manipulating TLRs is likely to be successful in fighting off different diseases.

/pdf/therapeutic-targeting-of-toll-like-receptors-for-infectious-4u7ahyljh8.pdf

Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20839

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection

ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.

Discovery of ANA975: an oral prodrug of the TLR-7 agonist isatoribine.

Isatoribine, a toll-like receptor 7 agonist, significantly reduced plasma viral load in a clinical proof-of-concept study in patients with chronic hepatitis C virus infection.

O.106 Pharmakokinetics, safety, tolerability, and pharmacodynamics of the isatoribine oral prodrug ANA975 in a multidose phase 1 healthy volunteer study

Bradley M. Kerr

Papers

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection

Discovery of ANA975: an oral prodrug of the TLR-7 agonist isatoribine.

Isatoribine, a toll-like receptor 7 agonist, significantly reduced plasma viral load in a clinical proof-of-concept study in patients with chronic hepatitis C virus infection.

O.106 Pharmakokinetics, safety, tolerability, and pharmacodynamics of the isatoribine oral prodrug ANA975 in a multidose phase 1 healthy volunteer study