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Transcript of Global distribution and prevalence of hepatitis C virus genotypes Hepatology Volume 61, Issue 1,...
![Page 1: Global distribution and prevalence of hepatitis C virus genotypes Hepatology Volume 61, Issue 1, pages 77-87, 28 JUL 2014 DOI: 10.1002/hep.27259 .](https://reader036.fdocuments.net/reader036/viewer/2022062304/56649e575503460f94b4f939/html5/thumbnails/1.jpg)
Global distribution and prevalence of hepatitis C virus genotypes
HepatologyVolume 61, Issue 1, pages 77-87, 28 JUL 2014 DOI: 10.1002/hep.27259http://onlinelibrary.wiley.com/doi/10.1002/hep.27259/full#hep27259-fig-0001
>3 million US> 100 million worldwideblood
https://serendip.brynmawr.edu/oneworld/virus
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HCV Genome 9 kb Flavivirus +RNA single strand
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Polyproteinprotease
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Protein Functions
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HCV life cycle
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HCV—Hepatitis C
PLOS Neglected Tropical Diseases 7, #9, 2435
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Abstract/ Conclusions
HCV patients 20/157
Median age 32 yearsFever 10Jaundice 7Hemorrhage 2
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PCR Diagnosis
Target amplicon
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HCV and Liver Function
• 13 patients• 92% low serum albumin• 77% high aspartate aminotransferase• 85 % high lactate dehydrogenase• 38 % high urea nitrogen
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HCV PhylogenyN. Ghana
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Science 13 February 2015:Vol. 347 no. 6223 pp. 771-775
Structural basis for RNA replication by the hepatitis C virus polymerase
Todd C. Appleby1,*, Jason K. Perry1, Eisuke Murakami1, Ona Barauskas1, Joy Feng1, Aesop Cho1, David Fox III2, Diana R. Wetmore2, Mary E. McGrath1, Adrian S. Ray1, Michael J. Sofia1, S. Swaminathan1, Thomas E. Edwards2,*
- Author Affiliations
1Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. 2Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
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Gilead—liver pipeline
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sofosbuvir
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Crystallography—in Ghana?
Clone,Express,PurifyProteins
Lots OfComputerWork
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HCV Polymerase-RdRp-NS5B
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Active site-2 RdRps—same structure
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HCV-RdRp-Initiation Complex
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Active site
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Elongation Complex-deleted B-loop
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Sofosbuvir—replaces substrate, but H bonds disrupted
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Initiation to ElongationDoes structure support kinetics data?
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Tuberculosis-Science 328, 2010, 852
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• “Tuberculosis, TB, is a disease that, in the Western world, is held in check by effective public health systems that compensate for the relative shortcomings of current intervention strategies.”
• “It is only through the combination of drugs, vaccines, and public health surveillance that we can hope to break the cycle of transmission whereby each TB patient is responsible for one or more new cases of the disease.”
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Bio-markers for disease progression needed
PET Sca18F-dGlucos
CAT Scan
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Discovering New Antibiotics
• Target TB—Mycobacterium tuberculosis– (10%)
• Screen natural soil extracts for selective anti-TB activity (Staphylococcus aureus) (30%)
• Lentzea kentuckyensis DQ291145 –lassomycin (2%) (selectively kills TB
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April, 2014, Vol 21, 509-18.
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Lassomycin Structure.
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Lassomycin operon
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Lassomycin activity against TB
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Lassomycin Activity against non TB
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Lassomycin vs exponential or stationary TB
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Complete genome sequencingtarget Lassomycin resistance mutations ClpC1 ATP dependent Protease
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Activity/Specificity Assays
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Docking Lassomycin , electrostatic and thermal maps (N-ter only)