Novel Synergistic Antimalarials with Resistance Reversal Function

具有耐药逆转功能的新型协同抗疟药

• 批准号: 10534667
• 负责人: JANE X KELLY
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534667
• 关键词: Address; Ames Assay; Antimalarials; Area; Binding; Biological; Biological Assay; Blood; Caco-2 Cells; Cardiotoxicity; Chemical Exposure; Complex; Cytochrome P450; DNA analysis; Disease; Dose; Drug Combinations; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Drug toxicity; Effectiveness; Environment; Evaluation; Fever; Genomic DNA; Goals; Health; Heme; HepG2; Human; In Vitro; Individual; Infection; Isoenzymes; Lead; Liver Microsomes; Malaria; Measures; Medical; Metabolic; Methods; Microsomes; Military Personnel; Mission; Modeling; Modernization; Molecular; Molecular Target; Monitor; Multi-Drug Resistance; Mus; Parasite resistance; Parasites; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Preclinical Testing; Research; Resistance; Rodent; Rodent Model; Safety; Salmonella typhimurium; Soldier; Toxic effect; Toxicity Tests; Vacuole; Validation; Veterans; Woman; Work; chemical synthesis; cytotoxicity; design; drug development; genome analysis; genome sequencing; improved; in vivo; innovation; iterative design; lead candidate; lead optimization; men; metabolic profile; military service; new combination therapies; novel; novel strategies; operation; patch clamp; pre-clinical assessment; pre-clinical research; preclinical safety; prevent; programs; resistant Plasmodium falciparum; safety assessment; single molecule; synergism; trait; uptake; whole genome

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. The devastating situation is largely attributed to and aggravated by the emergence and spread of multidrug- resistant Plasmodium falciparum, the cause of the deadliest form of malaria. Preventing and delaying emergence of drug-resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug resistant malaria. The novel chemotype described in this proposal represents a revolutionary approach. It specifically aims to exploit the strengths of other compounds with ideal traits by making possible a new combination therapy strategy. Our innovative design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. Our proposed work in this application seeks to develop novel, potent, safe, inexpensive, and sustainable antimalarial that can be co- formulated with other antimalarials in a synergistic combination to treat malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to maximize the antimalarial potential of the dual- function acridone chemotype through structural optimization for potency, synergy, pharmacology and metabolic stability; to accomplish preclinical assessment of lead candidates that are developed through this program of research; to evaluate for safety, to investigate the mode of action(s) for these synergistic antimalarial acridones, and to explore the propensity for drug resistance to selected acridone candidates.

尽管为根除疟疾作出了广泛努力，但疟疾的全球影响仍然令人震惊。的