Given that the number of cases of ebola in Africa is rising exponentially, and given that ZMapp is not going to be available in sufficient quantities any time soon, is it possible to find/screen for a small drug entity or protein aptamer that would interfere with the oligomerization of ebola matrix proteins or inhibit the action of other ebola virus proteins?
I think the answer is yes. The RCSB, the publicly available repository of protein structures, has over 40 ebola virus proteins, some deposited this year. I have to assume that someone(s) is screening ACD or other compound databases with docking programs to find potential hits. It would be great if those of us who used to do this type of work would also be able to contribute.
However, while the structures are available, and much work can be done just using the structures, the papers that are associated with them frequently are not. The journals involved can charge up to $33/copy for each paper. This cost is prohibitive for most independent researchers. Come to think of it, so are the applications I used to use to dock libraries of compounds into structures. But even with the limited public software, we could still get a lot done if we were able to read the papers for free. Like I said, reading the structure papers is not absolutely necessary but it can be helpful.
So, if there is anyone out there who has influence with PubMed, could you look into it? Also, is anyone aware of a crowdsourcing effort to design drugs based on these structures? Just give a shout out if you know of one.
One more thing: It would be very helpful to know the latest mutation data in FASTA format in case homology models need to be created on currently available crystal structures. I see that the octamer was crystallized in 2002 and is from strain Zaire Mayinga. If I’m not mistaken, the current epidemic is from a different strain. (though this protein may be more resistant to mutations? Dunno. Need to read the papers.)
Filed under: General | Tagged: crowdsourcing, ebola, oligomers, protein aptamers, protein structures, RCSB |
The Confluence 
(Off topic, but too good not to share)
You never know what’s going to inspire someone. The final scene of ‘Dirty Dancing’ did it for this little boy. His mother posted it to Facebook last week and it has over 9 million views already.
Have you seen it? It’s great 🙂
Ick! It’s mostly beta sheet. A paptamer might be tougher that I thought. Well, that’s just the first structure. There are only 46 more structures to look at…
I wish I could talk about this — it’s so interesting. But, I don’t know the language at all.
FASTA is a format for amino acid sequences. Every protein has a sequence of amino acids and they are all unique. Families of proteins are related to one another. You can perform an evolutionary trace on a single protein if the sequence of that protein over time has been determined. The FASTA sequence is stored in publicly available databases. The NIH allows access to these sequences for researchers and provides tools to search them. One of these search tools is called BLAST. It can do sequence alignments. So, if you have a fragment of a sequence or a new sequence, you can search the database to find the entire sequence or similar sequences. I used to use a related tool called BLASTp. That allows the user to find protein sequences that have been crystallized and are stored at the RCSB.
So, let’s say you have a protein that you know has mutated away from its original source. In this case, we are talking about the ebola viral proteins. The crystal protein I referred to last night was from a strain found in Zaire, in a place called Mayinga. But the newest outbreak of ebola is located in West Africa and it is a different strain, therefore, different mutations in the amino acid sequence.
If you designed a drug based on the Zaire Mayinga strain, it may not be effective against the West Africa strain because the amino acid sequences may be different. But we can make a homology model of the new viral protein structure if we know where the new mutations are. It’s the next best thing to a experimentally determined crystal structure.
The questions to ask are: do all of the viral proteins mutate at the same rate? We would know by looking at the latest FASTA sequences and mapping them onto the structure. Can we identify a binding site? The protein I looked at yesterday processed RNA. I can make an educated guess as to where this occurs. But when it oligomerizes, that is, forms a new structure by self assembly, it has a couple of different binding sites. That is, the binding sites of each subunit to the subunits adjacent to it can also be targeted for drug design. I worked on a different oligomer previously and it was possible to create a drug like entity called a pap tamer by extracting a chunk of the secondary structure of the subunit and modifying it very slightly. This prevented the subunits from self assembly, or so the theory goes.
But in the ebola protein I looked at yesterday, the protein-protein interactions between subunits were dominated by beta sheets, which relate to one another along parallel and antiparallel strands. So, extracting a piece of this binding surface would be difficult if not impossible. Another, more complex and time consuming drug design process would need to be done. If it were just a matter of a helix, it might have been a different story. So, this viral protein might not be amenable to quick and dirty drug design work and it might have to be abandoned for another ebola protein.
In any case, the FASTA sequence is very informative. It has likely been deposited at the NIH. They usually do that for Flu viruses and you can track mutations as they zip around the world. But I’m not sure we have the latest info for ebola.
Whew! That was long. Hope that caught you up with the lingo a bit.
Off topic: Toon mocks anti-vaxxers.
http://s175.photobucket.com/user/drkarma/media/Anti-vaccinationparodytoon_zps1222da27.jpg.html
This statement, which the Dallas hospital nurses funneled through National Nurses United, was read just now on CNN. It is one of the most shocking documents I’ve heard.
But, I can’t find a written copy of the text. It’s possible that the Nurses union will post it later today but they haven’t yet.
If someone finds it and posts the text to it I’ll make a post out of it.
This being the USA, the fault probably lies with some measure or measures taken to maximize profit for the stockholders. 👿
Possibly, but I don’t see how stockholders benefit by putting ebola specimens in the pneumatic tubes used by the entire lab system in the hospital.
How about: Health care workers making mental mistakes due to fatigue, because the company tries to get along on the bare minimum of workers, so the workers it does have are overworked?
I have friends in two towns nearby that are on the Boards of their hospitals. One had to close the maternity section. The state of IL is not paying their bills, and somehow, the hospitals still have to pay employees, etc. When you live in a town where 73% of the school kids are at poverty level, you know that most of those going to the hospital are on Medicare or Medicaid. If the state doesn’t pay the bills, what are they to do? If ebola hit one of those hospitals, it would bankrupt them.
Cynic,
If ebola hit one of those hospitals, it would spread around fast within it and then beyond it . . . .
unless CDC and the branches of Armed Services with relevant HazMat and decontamination skills and tools showed up soonest to take completely over.
Kbird, feel free to write a post on it if you want. I’d really love to read your reactions.
I want to, but I’ve got to get the quotes.
I read that CNN article late last night and I was shocked but not surprised, if that makes any sense. Shocked because the hospital was caught so unprepared and was really botching it. But unsurprised because it made a lot of sense in how the infection was spread to this nurse. No health care worker in their right mind wouldn’t take the utmost precautions given the media frenzy over ebola. I could only conclude that the hospital itself was at fault for being caught off guard and, probably, considering cost over treatment protocol. After all, who was going to pay to isolate Thomas Duncan? Rick Perry turned down medicaid expansion and the Texas legislature has severely cut back on state board of health offices. Laissez faire apparently means anything goes when it comes to profiting off of health care and Duncan was a money sink.
I think when they refer to the 90 minutes gap where Duncan was with other patients before he was isolated referred to the emergency room. Here’s my best guess: The ambulance dumps Duncan off at the ER with a barf bag. He has to sit there with other sick patients while calls are being made to the hospital administrative staff to decide how to admit him. He’s a foreign visitor, not even an immigrant, with no health insurance, dumped on Texas Health Presby Hospital. He doesn’t qualify for Obamacare, there’s no medicaid for him either because, hellloooo, Americans, especially those living in the south, don’t want to pay for the health care needs of foreigners. Are there funds set aside in Texas to manage a highly infectious disease like ebola? Are you kidding?? Decisions, decisions. The hospital might have thought of transferring him elsewhere but I’m betting the other facilities said they were no better able to care for him. It’s your problem.
Damn, Duncan could wipe out the profit for the entire year, what with the isolation and ruining ventilation and dialysis equipment, not to mention how to get rid of hazardous waste.
So, he sat in the ER for 90 minutes, vomiting and sweating all over the chairs and gurneys, before the hospital decides it doesn’t have a choice anymore and has to take him. Who knew how many people came in contact with him while he was shedding billions of viruses? Poor Nina Pham probably did what she was instructed to do with very little CDC oversight.
One other thing: I watched a symposium from Johns Hopkins yesterday and one of the speakers, Peter Jahrling, showed all of the possible drug treatments in the pipeline. It’s a joke. No, seriously. ZMapp looks like the best bet but the company can only make about 20 doses in its next batch. It’s not their fault. They’re just overwhelmed by the scale and logistics.
A couple of vaccines are being tested in the field. And they have to have a control group so 1/3 of the participants is getting Hepititis C vaccine. It can’t be helped but the participants must know that some of these people are going to die. There’s no way around it. That’s the way science is done. And these vaccines are not in anyway ready for FDA approval.
Other treatments are even less ready. Interferon actually makes the infection worse. There’s an interesting research topic. What is it about the cell signaling that makes interferon treatment worse? Then there are a couple of “drugs”. Honestly, I think biologists are analyzing the high throughput data. They think anything is a hit. The compounds presented may have some efficacy (probably in the millimolar range) but they’re not very bioavailable and the toxicity could be a major problem.
So, in short, we’re pretty much screwed if we can’t get West Africa back under control and the infection spreads.
Not that we have much to worry about here. We don’t. But it’s not very reassuring to me that we are sooooo far behind in the drug discovery area on infectious diseases. Again, shocked but not surprised.
The symposium can be found here. Most of it is School of Public Health academics trying to one up each other on modeling the progress of the disease. It got to be too insidery and less informative after awhile. Jahrling’s presentation was more straightforward, to the point and alarming. If the general public truly understood what Jahrling’s presentation was saying, they’d never vote for another Republican. Ebola is only one of a number of devastating infectious diseases that we are not prepared because we let private industry, dominated by shareholders and billionaires, dictate the research and manage the pipeline portfolios. It’s baaaaad.