Carl Nathan

There is a compelling need to find drugs active against Mycobacterium tuberculosis (Mtb). 4′-Phosphopantetheinyl transferase (PptT) is an essential enzyme in Mtb that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed’s ability to kill Mtb and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in Mtb from PptT to dihydrofolate reductase …

Mycobacterium tuberculosis (Mtb) can cause a latent infection that sometimes progresses to clinically active tuberculosis (TB). Type I interferons (IFN‐I) have been implicated in initiating the progression from latency to active TB, in part because IFN‐I stimulated genes are the earliest genes to be upregulated in patients as they advance to active TB. Plasmacytoid dendritic cells (pDCs) are major producers of IFN‐I during viral infections and in response to autoimmune‐induced neutrophil extracellular traps. pDCs have also been suggested to be the major producers of IFN‐I during Mtb infection of mice and nonhuman primates, but direct evidence has been lacking. Here, we found that Mtb did not stimulate isolated human pDCs to produce IFN‐I, but human neutrophils infected with Mtb‐activated co‐cultured pDCs to do so. Mtb‐infected neutrophils produced neutrophil extracellular traps, whose exposed DNA is a well …

The compounds of the present invention are represented by the following compounds having Formula I and Formula (I′):

2023-07-13 Assigned to TRI-INSTITUTIONAL THERAPEUTICS DISCOVERY INSTITUTE, INC. reassignment TRI-INSTITUTIONAL THERAPEUTICS DISCOVERY INSTITUTE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MEINKE, PETER T., LIANG, RUI, LIVERTON, NIGEL, GINN, JOHN, MICHINO, Mayako, SUN, SHAN, Huggins, David

NHJVRSWLHSJWIN-UHFFFAOYSA-N 2, 4, 6-trinitrobenzenesulfonic acid Chemical compound OS (= O)(= O) C1= C ([N+]([O-])= O) C= C ([N+]([O-])= O) C= C1 [N+]([O-])= O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 30

Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these diseases would benefit not just from new medicines and vaccines but also from a better understanding of what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon-γ (IFN-γ), a protein secreted by lymphocytes. Forty years ago, IFN-γ was identified as a macrophage-activating factor, and, in recent years, there has been a resurgent interest in IFN-γ biology and its role in human defense. Here we assess the current understanding of IFN-γ, revisit its designation as an “interferon,” and weigh its prospects as a therapeutic against globally pervasive microbial pathogens.

Expanded version of Table 3 from: “Interferon-γ and Infectious Diseases: Lessons and Prospects” by Jean-Laurent Casanova 1- Page 1 Expanded version of Table 3 from: “Interferon-γ and Infectious Diseases: Lessons and Prospects” by Jean-Laurent Casanova 1-5 *, John D. MacMicking 6-9 * and Carl F. Nathan10 * 1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University; New York, NY. 10065. USA 2 Howard Hughes Medical Institute; The Rockefeller University; New York, NY. 10065. USA 3 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France, EU 4 Paris Cité University, Imagine Institute, Paris, France, EU 5 Department of Pediatrics, Necker Hospital for Sick Children, Paris, France, EU 6 Department of Microbial Pathogenesis and 7 Department of Immunobiology, Yale University …

The compounds of the present invention are represented by the following compounds having Formula (I) and Formula (I′):