Biomod/2011/MIT/Origami/Malaria: Difference between revisions
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Structural Basis for the EBA-175 Erythrocyte Invasion Pathway <html><a href ="http://joshua-torlab.cshl.edu/pdf/Tolia-et-al-Cell.pdf">Link</a></html> | Structural Basis for the EBA-175 Erythrocyte Invasion Pathway <html><a href ="http://joshua-torlab.cshl.edu/pdf/Tolia-et-al-Cell.pdf">Link</a></html> | ||
This paper from 2006 details the invasion of red blood cells by malaria. Discussed are the initial interactions which are nonspecific but large in volume and then the proper orientation and entry into the cell, which can occur as fast as 60 seconds <html><a href="http://www.sciencedirect.com/science?_ob=MImg&_cid=272196&_user=501045&_pii=S0092867406001814&_coverDate=02%2F24%2F2006&view=c&wchp=dGLzVlt-zSkzk&md5=3be0493ea2cbcf69cb2c0108cb972578/1-s2.0-S0092867406001814-main.pdf"></a></html> | This paper from 2006 details the invasion of red blood cells by malaria. Discussed are the initial interactions which are nonspecific but large in volume and then the proper orientation and entry into the cell, which can occur as fast as 60 seconds <html><a href="http://www.sciencedirect.com/science?_ob=MImg&_cid=272196&_user=501045&_pii=S0092867406001814&_coverDate=02%2F24%2F2006&view=c&wchp=dGLzVlt-zSkzk&md5=3be0493ea2cbcf69cb2c0108cb972578/1-s2.0-S0092867406001814-main.pdf">Link</a></html> | ||
==Available Treatments== | ==Available Treatments== | ||
Revision as of 19:34, 2 November 2011
Malaria Literature
Malaria Mechanism Revealed A protein on the surface of the parasite, EBA-175, binds to glycophorin A, a receptor protein on the surface of red blood cells. If the parasite doesn't bind soon after it is released from the liver cells, it dies. EBA-175 has two RII molecules that come together resembling a handshake. The overall shape resembles a donut with two holes. This handshake interaction attaches the parasite protein onto the glycophorin A receptor. <html><a href="http://www.bnl.gov/bnlweb/pubaf/pr/PR_display.asp?prID=05-X15">Link</a></html>
Structural Basis for the EBA-175 Erythrocyte Invasion Pathway <html><a href ="http://joshua-torlab.cshl.edu/pdf/Tolia-et-al-Cell.pdf">Link</a></html>
This paper from 2006 details the invasion of red blood cells by malaria. Discussed are the initial interactions which are nonspecific but large in volume and then the proper orientation and entry into the cell, which can occur as fast as 60 seconds <html><a href="http://www.sciencedirect.com/science?_ob=MImg&_cid=272196&_user=501045&_pii=S0092867406001814&_coverDate=02%2F24%2F2006&view=c&wchp=dGLzVlt-zSkzk&md5=3be0493ea2cbcf69cb2c0108cb972578/1-s2.0-S0092867406001814-main.pdf">Link</a></html>
Available Treatments
There are currently three main classes of drugs that are used to treat HIV infection, all with different mechanisms of action. There are the reverse transcriptase inhibitors, the entry/fusion inhibitors and the protease inhibitors. There is also another class of drugs called integrase inhibitors, but there is only one type of this drug approved by the FDA and it is relatively new, and there is research being conducted on another class, the maturation inhibitors, but for the moment we'll focus on the first three classes.
Reverse Transcriptase Inhibitors
Among these, there are two classes, the Nucloside analog reverse-transcriptase inhibitors(NRTIs) and the Non-nucleoside reverse-transcriptase inhibitors(NNRTIs). NRTIs are similar in function and structure to natural nucleotides, and they compete with nucleotides to be added to the growing cDNA chain during reverse transcription, but since they lack a 3' OH, their incorporation into the strand causes a chain termination. NNRTIs on the other hand are allosteric inhibitors of reverse transcriptase, they bind to domains of the enzyme that hinder conformational changes required for adequate polymerization of the growing DNA strand. The problem with these is that they bind to a less conserved pocket of the p66 subunit(RT consists of a p66 and p51 subunits) which may make it more likely for the virus to develop resistance.
Entry/Fusion Inhibitors
There are two of these types of drugs that are FDA approved, enfuvirtide and maraviroc, each with it's own target. Maraviroc is an allosteric modulator of CCR5. It appears to cause changes in shape that inhibit the ability of viral glycoproteins to interact with it. It would therefore have no effect on strains of HIV that use CXCR4 as a coreceptor, but 80% of HIV strains use CCR5. Enfuvirtide acts by mimicking normal HIV-cell interactions to prevent said interactions from actually occurring. It binds to gp41 to prevent it from fusing the viral and cellular membranes. Downsides of Enfuvirtide include it's cost(around 25,000 per year in the US) and the fact that it is not available in an orally administered form, it must be injected. It is generally used only when a patient has developed resistance to other drugs, because the regimen is difficult to follow.
Protease Inhibitors
Protease is responsible for cutting the newly synthesized proteins at the appropriate places to create the mature proteins of the HIV virus. HIV protease inhibitors (PI) block the HIV aspartyl protease, which cleaves the HIV gag and gag-pol polyprotein backbone at nine specific cleavage sites. Most PIs are designed to mimic a phenylalanine - proline peptide bond because three of the nine cleavages occur between a phenylalanine or a tyrosine and a proline. It has been found that PIs also inhibit inflammatory cytokine production and modulate antigen presentation and T-cell responses.
Target Ideas
