The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs.
Influenza virus is one of the largest public health concerns. There is no universal vaccine, and only a few small-molecule drugs are available for therapy and prevention of influenza virus infection. The surface of this virus has two major proteins: neuraminidase and hemagglutinin (HA). These proteins are targets for antivirals. Although antivirals such as oseltamivir exist that bind neuraminidase, a major reason that there is no small-molecule drug against HA is because most of its surface is highly variable, presenting a moving target for drug development.
We screened a diverse chemical library for compounds that selectively target the group 1 HA epitope of bnAb CR6261 through a binding assay that detects displacement of a CR6261-based designed small protein. Benzylpiperazines were identified as a major hit class, with JNJ7918 being the most promising candidate. Consistent with its binding to the functional HA stem epitope, this compound also neutralized influenza infection in vitro. Key chemical modifications were subsequently introduced to optimize binding and neutralization potency, as well as properties dictating metabolic stability and oral bioavailability, to finally afford JNJ4796. This lead compound binds and neutralizes a broad spectrum of influenza A group 1 viruses in vitro and protects mice against lethal and sublethal influenza challenge after oral administration.
So far, around a quarter of people infected during the outbreak of a new coronavirus have developed severe respiratory infections, and around 3 per cent have died. With the numbers still climbing alarmingly fast, many groups are already rushing to try to find treatments for the virus. A vaccine that stops people being infected by the new coronavirus would obviously be better than any treatment, but that is some way off. "A vaccine would take at least a year, if not more," says virologist Jonathan Ball at the University of Nottingham in the UK. The good news is that a few existing drugs might help save lives in the meantime.
Progressive kidney diseases are often associated with scarring of the kidney's filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats.