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Abstract.: This paper aims to explore the impact of future flexible working model (FWM) evolution on urban environment, economy and planning. Working models are changing, evolving over several decades towards flexibility and mobility. Major cities are witnessing emerging alternative workplace models, such as coworking spaces, digital working hubs, on-demand spaces, and office clubs. These trends inevitably bring significant changes of flexible working hours, modified workplace business operations, different urban facilities requirements, and new workplace location options. However there remains a lack of understanding of the impact of such flexible modern workplaces on urban development. To address this issue, the current paper adopts a systematic literature review method, discusses the historical evolution and various types of FWM, and explores the impact of such FWMs on urban environment, economy and planning. This research leads to enhanced understanding, planning and management for the future challenges of next-generation working models in major cities, and brings potential direct benefits to urban development and the economy. Keywords: Flexible working model, Systematic literature review, Urban environment, Economy, Urban planning

Many small molecules have been identified as entry inhibitors of filoviruses. However, a lack of understanding of the mechanism of action for these molecules limits further their development as anti-filoviral agents. Here we provide evidence that toremifene and other small molecule entry inhibitors have at least three distinctive mechanisms of action and lay the groundwork for future development of anti-filoviral agents. The three mechanisms identified here include: (1) direct binding to the internal fusion loop region of Ebola virus glycoprotein (GP); (2) the HR2 domain is likely the main binding site for Marburg virus GP inhibitors and a secondary binding site for some EBOV GP inhibitors; (3) lysosome trapping of GP inhibitors increases drug exposure in the lysosome and further improves the viral inhibition. Importantly, small molecules targeting different domains on GP are synergistic in inhibiting EBOV entry suggesting these two mechanisms of action are distinct. Our findings provide important mechanistic insights into filovirus entry and rational drug design for future antiviral development., Competing Interests: The authors have declared that no competing interests exist.

Filoviridae, including Ebola (EBOV) and Marburg (MARV) viruses, are emerging pathogens that pose a serious threat to public health. No agents have been approved to treat filovirus infections, representing a major unmet medical need. The selective estrogen receptor modulator (SERM) toremifene was previously identified from a screen of FDA-approved drugs as a potent EBOV viral entry inhibitor, via binding to EBOV glycoprotein (GP). A focused screen of ER ligands identified ridaifen-B as a potent dual inhibitor of EBOV and MARV. Optimization and reverse-engineering to remove ER activity led to a novel compound 30 ( XL-147 ) showing potent inhibition against infectious EBOV Zaire (0.09 μM) and MARV (0.64 μM). Mutagenesis studies confirmed that inhibition of EBOV viral entry is mediated by the direct interaction with GP. Importantly, compound 30 displayed a broad-spectrum antifilovirus activity against Bundibugyo, Tai Forest, Reston, and Měnglà viruses and is the first submicromolar antiviral agent reported for some of these strains, therefore warranting further development as a pan-filovirus inhibitor.