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A Novel Cellular Target for Treating Influenza Virus Infections
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A3851 - A Novel Cellular Target for Treating Influenza Virus Infections
Author Block: X. Zhou1, L. Zhu2, Y. Chen3; 1pharmacy, Univerisity of Arizona, Tucson, AZ, United States, 2University of Arizona, Tucson, AZ, United States, 3Univ of Arizona, Tucson, AZ, United States.
Abstract: Influenza virus is the major cause of influenza (or flu). It has been the most important infectious pathogen in history and in the modern world. Influenza is one of the ten leading causes of death in the United States and its occasional pandemic killed millions of people around the world. The present anti-influenza measurements such as vaccination and antiviral drugs all have significantly limitations such as severe side effects or emergent resistances. Thus, new treatments for influenza viral infection are urgently needed. In our study to understand the life cycle of influenza infection, we serendipitously discovered a small molecule kinase inhibitor that had a unique off-target effect against GBF1, a Golgi specific guanine-nucleotide exchange factor for Arf family of small GTPase. Targeting GBF1-ARF1 had a broad-spectrum antiviral activity against multiple strains of influenza. We further demonstrated that the inhibition of GBF1 oligomerization, thereby affecting Golgi-mediated viral protein transport, was responsible for this antiviral effect. Additionally, this blockade also repressed influenza induced inflammatory responses, which oftentimes causes severe pathophysiological response even in the absence of active viral production. Therefore, further understanding of the mechanism through which GBF1-ARF1 regulates influenza life cycle and its induced inflammation will be beneficial for the development of novel therapy for treating influenza.
Author Block: X. Zhou1, L. Zhu2, Y. Chen3; 1pharmacy, Univerisity of Arizona, Tucson, AZ, United States, 2University of Arizona, Tucson, AZ, United States, 3Univ of Arizona, Tucson, AZ, United States.
Abstract: Influenza virus is the major cause of influenza (or flu). It has been the most important infectious pathogen in history and in the modern world. Influenza is one of the ten leading causes of death in the United States and its occasional pandemic killed millions of people around the world. The present anti-influenza measurements such as vaccination and antiviral drugs all have significantly limitations such as severe side effects or emergent resistances. Thus, new treatments for influenza viral infection are urgently needed. In our study to understand the life cycle of influenza infection, we serendipitously discovered a small molecule kinase inhibitor that had a unique off-target effect against GBF1, a Golgi specific guanine-nucleotide exchange factor for Arf family of small GTPase. Targeting GBF1-ARF1 had a broad-spectrum antiviral activity against multiple strains of influenza. We further demonstrated that the inhibition of GBF1 oligomerization, thereby affecting Golgi-mediated viral protein transport, was responsible for this antiviral effect. Additionally, this blockade also repressed influenza induced inflammatory responses, which oftentimes causes severe pathophysiological response even in the absence of active viral production. Therefore, further understanding of the mechanism through which GBF1-ARF1 regulates influenza life cycle and its induced inflammation will be beneficial for the development of novel therapy for treating influenza.
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