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Structure-Based Drug Design of Influenza Neuraminidase Inhibitors: Discovery and Development of "TAMIFLU"

2006년 2월 15일 10시 44분 57초
금21E1심 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
금 13시 : 30분
의약화학 - 의약1. Development of Carbohydrate-Based Drugs
저자 및
Choung Kim
Chemistry Gilead Sciences, Inc., U.S.A.,
Influenza continues to be a serious concern with yearly epidemics causing significant morbidity and mortality. Control of highly pathogenic avian H5N1 influenza virus is a major issue of world-wide public-health. Influenza virus neuraminidase catalyses the cleavage of sialic acid residues terminally linked to glycoproteins and glycolipids and plays a key role in the replication of the virus. The rational design of mimicking the transition state of the sialic acid cleavage led to the discovery of GS 4071 as a potent influenza neuraminidase inhibitor. GS 4071 binds into the neuraminidase catalytic pocket different from sialic acid with the strong hydrophobic interaction at the glycerol binding site. Utilizing this hydrophobic interaction, GS 4071 was desighed to increase lipophilicity considerably compared to sialic acid for oral absorption. Further prodrug optimization of GS 4071 to GS 4104 (oseltamivir, TAMIFLU) as the ethyl ester was necessary for high oral availability in rats and dogs. GS 4104 exhibited potent neuraminidase activity against laboratory and clinical isolates of influenza A and B viruses in the low (<10) nanomolar range. GS 4104 also showed potent effects against influenza A and B viruses in animal infection models. Dosage of GS 4104 at 1 and 10 mg/kg/day significantly reduced virus titers in the lungs of mice infected with highly pathogenic H5N1 A/VN1203/04 influenza virus. Mechanism of resistance to GS 4104 will be discussed in this presentation.