Infections with the human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV) are among the most significant causes of human morbidity and mortality. Worldwide, there are more than 40 million (HIV-1) and 170 million (HCV) people infected with these viruses. In the United States, 0.6% (HIV-1) and 1.7% (HCV) of the population is infected. More than 25% of those infected with HIV are co-infected with HCV (up to 90% of i.v. drug users). Despite the success of highly active anti-retroviral therapy, there remains a need to develop additional drugs targeted to novel receptors that will ensure different susceptibilities to the development of resistance compared to protease and reverse transcriptase, the principal receptors of current drugs. In contrast, current therapies for HCV are wholly inadequate, and multiple first-generation drugs are needed. Resistance is quickly developed to drugs patterned after those effective against HIV-1. The genomes of both HIV-1 and HCV encode a viroporins, a small membrane protein with ion channel activity involved in the production of new virus particles in infected cells. We propose to take a structural approach to the design of drugs directed against these viroporins. This is technically challenging research because viroporins reside in cell membranes, and one of the most important things we have learned from our studies of membrane proteins is that they are distorted by membrane mimics, such as organic solvents and detergent micelles, and must be studies in their native phospholipid bilayer environment under physiological conditions. As part of this research we have developed a general NMR method for determining the structures of membrane proteins in phospholipid bilayers, and will apply it to these viroporins. Determining the native structures of Vpu (Virus protein """"""""u"""""""") from HIV-1 and the p7 protein from HCV are essential in order to understand the molecular mechanism of their biological activities and to accelerate the discovery of drugs that interfere with the activities that contribute to the infectivity of the virses. Because we express these proteins and domains of their cellular partners in bacteria, we have a great deal of flexibility in the design of experiments to characterize their interactions with both drugs and proteins.

Public Health Relevance

Most diseases that afflict humans can be treated or cured with drugs. The majority of therapeutic drugs are chemicals targeted to protein receptors that reside in cell membranes. This research is designed to utilize structural information on the viroporins Vpu from HIV-1 and p7 from HCV to accelerate the discovery of drugs that interfere with their functions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Sakalian, Michael
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Berkamp, Sabrina; Park, Sang Ho; De Angelis, Anna A et al. (2017) Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy. J Biomol NMR 69:111-121
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Park, Sang Ho; Berkamp, Sabrina; Radoicic, Jasmina et al. (2017) Interaction of Monomeric Interleukin-8 with CXCR1 Mapped by Proton-Detected Fast MAS Solid-State NMR. Biophys J 113:2695-2705
Yao, Yong; Dutta, Samit Kumar; Park, Sang Ho et al. (2017) High resolution solid-state NMR spectroscopy of the Yersinia pestis outer membrane protein Ail in lipid membranes. J Biomol NMR 67:179-190
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Park, Sang Ho; Wang, Vivian S; Radoicic, Jasmina et al. (2015) Paramagnetic relaxation enhancement of membrane proteins by incorporation of the metal-chelating unnatural amino acid 2-amino-3-(8-hydroxyquinolin-3-yl)propanoic acid (HQA). J Biomol NMR 61:185-96

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