Combating Human Pathogens and Cancer by Targeting Phosphoinositides and Their Metabolism

Microbial pathogens have evolved to subvert phosphoinositide-regulated processes throughout their life cycles. Phosphoinositide signaling is commonly dysregulated in almost all cancer types. The fundamental roles of phosphoinositides and their metabolizing enzymes in microbial infection and tumorigenesis offer promising opportunities for pharmacological targeting in these disease settings. Current phosphoinositide-modifying enzyme antagonists, despite largely low efficacy and toxicity, have achieved certain successes in anticancer therapies, while remaining underexplored in infection settings. The direct targeting of phosphoinositides, based on early studies on aminoglycosides and recent findings on phosphoinositide-dependent cell death effectors, may offer attractive alternative anti-infective and anticancer therapeutic approaches. Pathogens and tumor cells have adopted various adept strategies to evade immunosurveillance and promote their growth and survival. There has been substantial evidence demonstrating phosphoinositide lipids and their modifying enzymes as essential host targets that are often hijacked by pathogens and tumor cells. The common dependence of pathogen virulence and tumor progression on phosphoinositides presents an exciting disease-combating potential, particularly combinatorial therapeutics. While traditional approaches to pharmacologically inhibit phosphoinositide-metabolizing enzymes has shown some promise, the direct targeting of phosphoinositides has recently emerged as a novel therapeutic strategy. Our review provides a current picture of the role of phosphoinositides during pathogen virulence and tumorigenesis as well as a thorough discussion on promises, challenges, and new perspectives of phosphoinositide-targeting drug development. Pathogens and tumor cells have adopted various adept strategies to evade immunosurveillance and promote their growth and survival. There has been substantial evidence demonstrating phosphoinositide lipids and their modifying enzymes as essential host targets that are often hijacked by pathogens and tumor cells. The common dependence of pathogen virulence and tumor progression on phosphoinositides presents an exciting disease-combating potential, particularly combinatorial therapeutics. While traditional approaches to pharmacologically inhibit phosphoinositide-metabolizing enzymes has shown some promise, the direct targeting of phosphoinositides has recently emerged as a novel therapeutic strategy. Our review provides a current picture of the role of phosphoinositides during pathogen virulence and tumorigenesis as well as a thorough discussion on promises, challenges, and new perspectives of phosphoinositide-targeting drug development. a molecule that inhibits the function of a biologically active molecule. a form of programmed cell death characterized by the breakdown of cellular components and formation of membrane blebs prior to cell disassembly. a process by which a cell degrades and recycles its own cellular components. closure of membrane extensions to form a sealed phagocytic vesicle. transition, typically in a cancer setting, whereby epithelial cells lose adhesion factors and become motile, allowing them to migrate and invade neighboring tissue. process in which vesicles or membrane-bound organelles of the same type merge together to form one entity. segment of a protein that does not fold into a fixed secondary structure. the enzymatic breakdown of intracellular components within a lysosome. the process by which lysosomes merge with other vesicles to form one individual organelle. localized reorganization of actin filaments at the surface of a motile cell. compounds designed to mimic the structure of a known molecule in order to inhibit or activate the binding partner of the known molecule. controlled form of cell death which, in contrast to apoptosis, leads to an inflammatory response. Necroptosis is typically initiated in order to halt viral replication within a host cell. unprogrammed form of cell death in which cells lyse and induce an inflammatory response due to tissue damage. effect of a gene which, either through activation or inhibition, promotes the onset or development of a tumor cell. cellular engulfment of relatively large bodies (e.g., bacteria and viruses). a regulated form of inflammatory cell death that is executed by the effector molecule gasdermin D.