New Antibiotic Research?
An economist view on the lack of antibiotic research has identified the following action points:
· A global „innovation fund“ of around $2bn to support new ideas
· A reappraisal of existing drugs
· Reduce unnecessary prescriptions through better testing
· Train a new generation of scientists in the field
· Track how resistance is spreading
To realize the above we need pharma / biotech / academics to invest in new research initiatives now. When new antibiotics do become available, the payers will also need to appreciate that they will not be as cheap as the ones we have available today.
Bullets 2 & 3 will also require fast turnaround testing; in order to identify which of our current arsenal of antibiotics will be an effective treatment regimen.
Is this all wishful thinking or will action follow?
Follow up on yesterday’s posting
Some further thoughts on yesterday’s posting. I am not a biologist/geneticist, so this is just my thinking out loud.
Mitochondria are only passed on down the maternal line in the egg; there are no mitochondria in sperm as I understand it. If the mother is healthy, then you must assume that the mitochondria contained in her cells are heterogeneous in genotype and that so called “mitochondrial disease” mitochondria are recessive. At any given cell division event, mitosis or meiosis, then there is also a partitioning of the mitochondria into the 2 daughter cells. This partitioning we must assume to not be uniform, to result in eggs and embryos exhibiting a phenotype of mitochondrial disease.
Therefore in the 3 parent IVF proposal the researchers must be confident of being able to screen all “mitochondria disease” mitochondria in the donor egg or embryo and that they are the sole cause of the phenotype called “mitochondrial disease”.
How to overcome Mitochondrial Diseases
The UK parliament has voted to allow 3 parent IVF to overcome inherited mitochondrial diseases. There are lots of ethical debates one could have on the subject and I would have loved to have heard the debate live than read snippets afterwards. In the BBC commentary it seems that there was a debate on whether this comes under “genetic modification” – as defined as a legal term.
In the cartoon below, grabbed from the BBC site but original attributed to HFEA, the depiction suggests 2 nuclei in the embryo cell which is thoroughly incorrect, only 1 nucleus per cell. Also there is no indication of the male donor, used to fertilize the donor egg, to generate a donor embryo. So in theory we could be allowing a 4 parent IVF baby.
The alternative proposed method, would be a 3 parent IVF and the cartoon is clearer.
Drug Delivery Reward
A Pioneer of drug delivery has been rewarded with a Queen Elizabeth Prize for engineering of £1m. The award recognizes the contributions made by Professor Robert Langer, in targeted drug delivery by a whole host of implant devices, which have benefitted billions of patients worldwide.
When DMPK limits oral dosing or systemic adverse effects are observed, targeted drug delivery mechanisms can circumvent these hurdles to a beneficial therapy.
Helium or Hydrogen
Both Hydrogen and Helium gases have been used to provide lift in gas balloons. Although since the Hindenburg disaster, Hydrogen has, in the main, been avoided. New World records have been set over the weekend by Two Eagles project for gas balloons.
During reporting on BBC Breakfast (Saturday) there was confusion over whether the balloon was Helium or Hydrogen filled. The presenters launching the discussion about Helium balloons with balloonist Don Cameron who responded that the balloon was filled with Hydrogen as it was cheaper / more plentiful, also the pilots could not cook or have a naked flame in the basket, due to Hydrogen flammability.
Now as a chemist there is a big difference between Hydrogen and Helium, not just flammability AND as an organic chemist Helium is a precious commodity for keeping the NMR magnet cool. Helium constantly escapes the earth’s atmosphere, so is getting rarer all the time.
Carbon – Fluorine Bonds
Relative bond strengths are fundamental in determining reaction pathways and in medicinal chemistry, where your potential drug molecule, may have metabolic liability. A technique often employed by medicinal chemists, when a site of metabolism has been identified, is to block by substituting hydrogen for fluorine. The carbon – fluorine bond being much stronger than carbon – hydrogen bond. Have you tried reacting an acid fluoride lately?
Stronger though does not mean unreactive, under the appropriate conditions transformations can occur. A timely reminder is printed in Tetrahedron Letters (2015) p877-883, where the authors review the reactivity of allylic mono/di/tri fluoro and benzylic trifluoro groups. Some of the reaction conditions are surprisingly mild 25-75 C.
Anticholinergics and Alzheimer’s
Unfortunately I have not been able to view the original article, JAMA Internal Medicine. However, the reporting in the popular media, as a scientist, is all alarmist.
The headlines shout of anticholinergic increasing risk of Alzheimer’s by 50%, but neglect to inform on what the baseline risk is, so the casual reader is unable to make an informed judgement. This is important as a number of the alleged mendicants are OTC products. You also have to take account of the other observations of “top dose” and chronic taking for 3 years.
“Dr Simon Ridley, at Alzheimer’s Research UK, said: “This large study adds to some existing evidence linking anticholinergic drugs to a small increased risk of dementia, but the results don’t tell us that these drugs cause the condition.”
Indeed the other interpretation could be that the conditions being treated by the anticholinergics may be the first signs of a pre-disposition to Alzheimer’s.
Ebola in West Africa
A topic I have been trying to get my head around for a while. The current outbreak has been on going, I believe, for over a year. Last summer there was a ground swell of opinion that something had to be done. The World Health Organization agreed to fast tracking therapies into humans. Last week GSK made the first shipment of an experimental Ebola vaccine.
As stated in the BBC article, new cases are already in decline due to improved hygiene regimes. So, careful analysis of the vaccine and other treatment outcomes will be required. Indeed it would be unethical to have a placebo arm for such a lethal disease. Anti-Ebola treatments will never be blockbusters, as those most affected live in the poorest parts of the world, but it is welcome to see the pharma of the world rallying to help.
A wider question follows, a large constituent of drug cost are the clinical trials, to get a license to sell as a medicine. Now we don’t want another thalidomide, but is our current regulatory system too restrictive? It is after all the human animal we want to treat / cure, whilst still being mindful to “first do no harm”.
You’ve designed the molecule you want to synthesis. Next to hit the chemical catalogues – hardcopy or electronic. The planned synthesis extends back until a feedstock is a) listed & b) available to purchase in a reasonable timeframe. All the chemicals listed will have been made by skilled chemists. I have recently read “The Chemists’ War: 1914-1918” by Michael Freemantle, the book brings in to focus how far chemistry has come over the last 100 years. The availability of feedstock’s: how do you make acetone! All carried out without our now ubiquitous LCMS/NMR characterization.
Researchers at Roche report an interesting transformation in Tetrahedron Letters 2015 p775-778. The graphical abstract and Letter title lure you in, as both a medicinal and synthetic chemist. The authors are open and say the reaction was found by isolating & characterizing a compound and finding it not to be their intended reaction product. The isolated compound and desired compounds are isomeric so you could ask whether diligent spectroscopic analysis [possibly an N.O.E.] or change of anticipated biological activity was the trigger for further investigation. Either way the observation led to further chemical investigation and ultimately this journal article.
May be this should be a reminder that a proton NMR and LCMS are not always sufficient to prove identity of compounds synthesized!
Alzheimer’s Disease R&D
The amyloid beta hypothesis has been around a long while now, with many companies making inroads into brain penetrant inhibitors of BACE1. A good review of the area can be found in Bioorganic & Medicinal Chemistry Letters 24 (2014) 2033–2045.
New reports suggest attenuating BACE1s aberrant activity by changing its glycosylation state, inhibiting a process up stream. The researchers have found that the enzyme GnT-III is responsible for the glycosylation of BACE1, which leads to APP being processed to amyloid beta.
Back to the Grindstone!
“Mechanochemistry” is having a renaissance according to an article in January 2015 Chemistry & Industry by XiaoZhi Lim. Mechanochemistry is defined reactions performed in the absence of solvent by the action of grinding. Back in the days of alchemy, a pestle and mortar were employed, today a ball-mill. Anhydride opening, Michael reaction and Aldol reactions are quoted as being readily performed under mechano conditions.
As a medicinal chemist, I have observed the effects of grinding in heterogeneous reactions, where a base such as potassium carbonate is out of solution. On a small lab-scale the solid may be ground up by the magnetic follower, however, as you scale up the synthesis and employ an overhead stirrer the reaction co-ordinate may change due to the more granular solid base.
New Companies fill where Major Pharma Contracts
As major pharma contracts, new companies start. Back in 2010, RedX pharma started in one therapeutic area. Today, Jan 2015, they are in anti-infection and oncology. Soon they will launch on to the stock market, to fund their research sustainably and to launch a third therapeutic area –immunology.
“If we knew what it was we were doing, it would not be called research, would it?” ― Albert Einstein
The above quote is generally well known amongst scientists. But when something is generally known, it does NOT mean everyone knows it, e.g. Chemistry World Jan 2015, Opinion piece by Derek Lowe.
A few “Known Unknowns”:
1) Magnesium sulfate is acidic, so don’t use to dry a solution of a basic compound, use sodium sulfate which has a neutral pH.
2) PPE – gloves let chemicals through before they physically fail / fall apart – you should change them at the first sign of contamination.
3) MSDS/COSHH assessments only tells you about the behaviour of pure substances, not how they will behave in the reaction mixture you propose putting together. Full risk assessments consider all scenarios e.g. are gases evolved in the reaction.
4) Tert butyl methyl ether (TBME) does not readily form a peroxide, so is generally a safer alternative to diethyl ether.
AstraZeneca drug Brilinta, discovered by scientists at their former Loughborough site, has shown benefit in a study of patients who had a heart attack over a year ago.
Update – Cancer Drugs Fund in England
Cost benefit analysis was carried out by doctors, pharmacists and patient groups. There are currently 62 drugs on the fund from the new fiscal year, of which 3 are new to the list this year. However, 25 drugs have been removed from the list, which equates to 30% of the 2014-15 list.
Cancer Drugs Fund in England
Drug research costs money and the output product is a new drug treatment. Irrespective of the country / healthcare system someone picks up the bill for a course of drugs. Those picking up the bill look at the cost / benefit of the treatment. In England it has been acknowledged that new cancer treatments are expensive and so an additional fund was added to the healthcare budget to specifically fund these treatments. It looks now that some drug treatments are no longer going to be covered by the fund. It is unclear to me whether this is solely on cost grounds or from a review of cost / benefit analysis, either stand alone or versus new treatments for the same cancer.
This is all over the media today…………
All the media is abuzz with news of this potential new antibacterial. Bacterial cell walls are constructed of protein and fat. Current antibiotics target the protein component and resistance has grown against the class. Teixobactin is indicated to interrupt the fat component of cell walls, like current antibiotics leads to an unstable wall, which leads to bacterial cell lysis.
The structure is available on Wikipedia: http://en.wikipedia.org/wiki/Teixobactin an 11 amino acid short peptide.
Bumper Year for New Drug Approvals – 2014
Lots of interesting material in this article: statistics; mergers/non-mergers; movers and shakers. As a medicinal chemist a couple of items stand out.
1) Of the 44 new approvals 16 are “First in Class”. New areas are always needed, but harder as no validation in the public domain. To get to approval these compounds were probably first made in their parent projects 6-10 years ago (2004-2008). The projects themselves likely began even earlier.
2) Of the 44 new approvals 28 are small chemical entities (not biologicals). Percentagewise biologics are up, but chemistry still dominates the field.
2 Knights for Chemistry in New Year’s Honours list
I worked in the same department as Simon Campbell, at Pfizer (Sandwich), in my industrial placement year as part of my undergraduate studies.
Possible new treatment for Rheumatoid Arthritis
Electrical stimulation to treat RA is in the news today (several daily papers and news streams), but scientific searches shows at least 12 months old. Interesting that not just pain, but inflammation/swelling also reduced by this nerve stimulation regimen. Device is implanted into the patient, so permanent, unlike a TENS machine that you may be familiar with from ladies giving birth or sports injuries.
Promise from a Medicines for Malaria Venture preclinical candidate (+)-SJ733
The clinical candidate is from a class of dihydroisoquinolone compounds, identified through high throughput phenotypic screening. Its mode of action appears to be the antagonism of the Plasmodium sodium ion pump, ATP4. This leads to raised concentration of sodium ions within the parasite, which affects its viability. This results in changes in the host red blood cell which marks it for destruction by the immune system. From my reading it is unclear if changes to the parasite by antagonism of ATP4 or lysis of the parasite within the host red blood cell (by raised intra-parasite sodium levels), bring about changes to the host red blood cell marking it for the immune system.
New compound shows anti-malaria promise
A newly developed anti-malarial compound can trigger the immune system into rapidly destroying red blood cells infected with the malaria parasite and, at the same time, leave healthy blood cells intact.
Interleukin-17A (IL-17A) is a protein that is found in high concentrations in skin affected by psoriasis, and is a target for investigational therapies. Click the infographic to learn how IL-17A impacts psoriatic skin and other parts of the human body.
Excellent news for the computational and cryptographical chemical community. A great repository to exploit:
A big landmark this week at the Cambridge Crystallographic Data Centre – 3/4 million structures in the Cambridge Structural Database!! Read all about it here: https://lnkd.in/dVdee4Y
750,000 structures and counting…
Back in 2012, when the number of structures in the Cambridge Structural Database (CSD) reached 600,000, Seth Wiggin, a Senior Scientific Editor at the CCDC suggested in his blog that we should put the champagne on ice for the…
Interesting 2 step transformation. Not very atom efficient. Will need to consider utility carefully for each case:
New reagent for methylation of heterocycles http://bit.ly/1D448VB
Methylation Made Simpler
C–H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase Some years ago, I had some laughs with a friend doing his PhD one bench away. He was working in HIV proteases, and he told me that talking to the…
Loughborough will be building on our strength in #STEM subjects with the newly announced STEMLab. It will be a state-of-the-art suite of teaching and learning space, made possible by a £5 million award from the Higher Education Funding Council for England. Read the full story: http://bit.ly/1CZlEKQ
Interesting article in Dec 2014 C&I from the SCI. Discussing different permutations for Europe grid, which has a high proportion of electricity generated by photovoltaic cells and a total solar eclipse on 20 March 2015. Article author Maria Burke.