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HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

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DuPontYoung Faculty Award as well as by DuPont Agrochemical, Amoco, and Hoechst Celanese Corporation. We acknowledge a generous loan of precious metals from Johnson Matthey Inc. We thank Supelco for a gift of a b-DEX GC column and Professor Tim Glass for helpful suggestions.PennPhos P,P'-1,2-phenylenebis(endo-2,5-dialkyl-7phosphabicyclo[2.2.1]heptane)

Background China has a large population; however, medical resources are unevenly distributed and extremely limited, and more medical services are needed. With the development and ever-increasing popularity of mobile internet communication, China has created a mode of mobile health (mHealth) care to resolve this problem. Objective The aim of this study was (1) to describe the problems associated with China’s medical care practice, (2) explore the need for and the feasibility of internet-based medical care in China, and (3) analyze the functionality of and services offered by internet-based health care platforms for the management of chronic diseases. Methods Data search was performed by searching national websites, the popular search engine Baidu, the App Store, and websites of internet medical care institutions, using search terms like “mobile health,” “Internet health,” “mobile medical,” “Internet medical,” “digital medical,” “digital health,” and “online doctor.” A total of 6 mobile apps and websites with the biggest enrollment targeting doctors and end users with chronic diseases in China were selected. Results We recognized the limitations of medical and health care providers and unequal distribution of medical resources in China. An mHealth care platform is a novel and efficient way for doctors and patients to follow up and manage chronic diseases. Services offered by these platforms include reservation and payment, medical consultation, medical education assessment, pharmaceutical and medical instruments sales, electronic medical records, and chronic disease management. China’s health policies are now strongly promoting the implementation of mHealth solutions, particularly in response to the increasing burden of chronic diseases and aging in the population. Conclusions China's internet-based medical and health care mode can benefit the populace by providing people with high-quality medical resources. This can help other countries and regions with high population density and unevenly distributed medical resources manage their health care concerns.