Zika virus: A neglected disease with no specifically designed drugs

I was shocked to see in recent weeks how a potential connection between a virus infection and  pregnant women have led to a global concern for the association with a high number of babies being born with microencephaly, initially in Brazil but with other cases shown worldwide, and it has even been associated to the rare Guillain-Barré Syndrome (1). Children with these syndromes are likely to have shorter life expectancies. A recent opinion article (2) with extensive research on this particular virus is analised in this blog.

After the epidemic outbreak of the Ebola virus in 2014-2015 which killed thousands of people in Africa and risked to generate a pandemic crisis, mobilising the World Health Organisation (WHO) and Governments, we have been exposed to another case of unprepared health concern with serious global implications.

Zika virus (ZIKV) is a virus from the Flaviviridae family with genetically similarities with the ones responsible for the Dengue Fever and the Yellow Fever. ZIKV was isolated and reported over 60 years ago and since then the small number of publications, the lack of a crystal structure, the abscence of reports of molecules having been screened either in vitro or in vivo in animal models, and the lack of patents covering drugs targeting ZIK virus (although there are some focused in compounds addressing the Dengue Fever), has left it as an undoubtedly case of a “Neglected Disease”.

So, despite of having some knowledge of the virus, little if not nothing seems to have been done in order to understand its risks, exposing under this circumstances, right now, its danger after the outbreak. The WHO has had to move faster than 2 years ago with the Ebola epidemic, and has  issued a Public Health Emergency of International Concern (PHEIC).

Ekins and co-workers(2), after extensive research on related viruses and taking into consideration antivirals and non-related drugs, suggest to create a fast-track plan of action in order to tackle the problem with more urgency, leadership and preparation. This could be applicable to other future outbreaks and put us in a better situation to fight future epidemics.

With the information we have on other closely related virus like the Dengue, the immediately plan of action against this outbreak should have to start with the use of already FDA-approved antivirals profiled against related viruses (with a safety and efficacy profile proved) as a starting point in fighting the ZIKV, and test other drugs, non antivirals and compounds from commercial sources (eg. Libraries) in a descendent order of priority as shown in Fig 1.


Figure 1. Compounds and chemical libraries suggested to be tested against Zika virus

Without much further do, the authors propose the following Drug Discovery plan:

  1. To develop a cell or ZIKV-target based in vitro assay, which might have to be done in special protective environments, limiting the number of companies or organisations capable of such as assays.
  2. The immediate test of all kind of available drugs (up to 48 FDA approved known antivirals) into the previously generated and validated assay, capable to produce some results against the absence of any other treatment, as reflected in Table 1.
  3. To study and understand the genome of the ZIKV and how a chemotherapy approach could lead to effectively target the virus.
  4. To develop and use “homology models” showing the suggested protein sequence based in similar/ related viruses with known molecule action-modes using target prediction software, such as SWISS-MODEL.
  5. To establish a pharmacological profile with a suitable/ ethical animal model


Table 1. List of potential compounds to tes.t

Equally important and without leaving it off the schedule, the scientific community should undertake efforts to reveal the virus structure, its function and physiology and establish the relationship between the infection and the human neurological abnormalities.

Despite of getting even better co-ordinating resources through management organisations like WHO, more should be addressed in an emergency outbreak from National Governments and Health Institutions through funding (eg. from the FDA repurposing approved drugs, from big pharmaceutical companies through the donation of chemicals to be tested, from biotechs investing in the development of ZIKV-based in vitro assays, from ground-field-experienced organisations like Medecins Sans Frontieres, etc…)

We need to retain alert against highly likely-to happen diseases lurking upon us at any time and learn from past actions to make us better prepared to fight them.

Blog written by: Jose Gascon


  1. Oehler E, Watrin L, Larre P, Leparc-Foffart I, Lastere S, Valour F, Baudouin L, Mallet HP, Musso D, Ghawche; Zika virus infection complicated by GuillainBarre syndrome–case report, French Polynesia, December 2013. Euro Surveill. 2014; 19(9): 20720
  2. Ekins S, Mietchen D, Coffee M, Stratton TP, Freundlich JS, Freitas-Junior L, Muratov E, Siqueira-neto J, Williams AJ, Andrade C; Open drug discovery for the Zika virus. F1000Research 2016, 5:150


Beer versus Alzheimer!

While casually browsing for updates on Alzheimer’s Disease (AD), apolipoprotein E4 (ApoE4) genotype and amyloid beta (Aβ) burden, one title strongly caught the attention of the author of this blog:

Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series.

Beer drinking against dementia? This study, published by Kok and colleagues (1) in Alcoholism: Clinical & Experimental Research, at least deserved reading! The authors investigate in this paper the association between the consumption of different alcoholic beverages (spirits, wine, beer) and Aβ aggregation in the brain. Their results rather surprising: beer drinking decreased the prevalence of Aβ-immunoreactivity in brain sections of autopsy cases investigated.

Before looking into details of the study, first a brief background on Aβ and AD. Amyloid plaques or senile plaques are extracellular deposits of the Aβ peptide and are one of the microscopically hallmarks of AD. The Aβ peptide is derived by sequential proteolytic cleavage of the β-amyloid precursor protein (APP) and plaques seem to spread hierarchically throughout the brain in patients with AD (figure 1). AD is a complex disease and little is known about its pathophysiology and cause. Also studies have shown a substantial genetic component in AD, the pattern of inheritance seems far more complex in which genetic risk factors such as ApoE4 work together with environmental factors and life exposure (i.e. life style).


Figure 1: Characteristic progression of Aβ deposition. Senile plaques (left) seem to spread hierarchically throughout the brain in patients with AD (right). Modified from Jucker et al(2)

Kok et al (1) investigated on how alcohol consumption may influence Aβ burden and analysed for this brain sections (frontal cortex) of 125 cases that were known to consume alcohol and of which Aβ data was available. Only beer drinking was negatively associated with the presence of Aβ-immunoreactivity (figure 2); spirits and wine did not show any correlation, and age, as well as ApoE4 genotype were, as expected, strongly associated with Aβ burden.


Figure 2: Aβ-immunoreactivity prevalence in beer drinkers versus non-beer drinkers (unadjusted analyses, n= 125).

The mechanism on how beer consumption may influence Aβ aggregation remains speculative. Regular beer consumers were shown to have increased levels of B vitamins and folate, as well as reduced levels of total homocysteine. High blood levels of homocysteine (hyperhomocysteinemia) seem to increase the risk for endothelial cell injury that may result in stroke and are associated with a wide range of diseases including thrombosis and AD (for review see (3)). However, how this links to Aβ burden clearly needs further investigation. Nevertheless, the study by Kok et al (1) is unique and is the first study that assesses the effects of alcohol consumption on post-mortem Aβ aggregation.

The author of this blog wants to emphasize that after reading this blog it is not advisable to drink more beer now. As most are surely aware, excessive use of alcohol can lead to cognitive impairment and many other undesirable things.


Blog written by: Lucas Kraft


  1. Kok, E. H., Karppinen, T. T., Luoto, T., Alafuzoff, I., and Karhunen, P. J. (2016) Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series. Alcohol. Clin. Exp. Res. 10.1111/acer.13102
  2. Jucker, M., and Walker, L. C. (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 501, 45–51
  3. Morris, M. S. (2003) Homocysteine and Alzheimer’s disease. Lancet. Neurol. 2, 425–8



Who Needs Lab-Based Synthetic Chemists?

Back in 2013 I was a postdoc at the University of Tokyo – when I wasn’t working hard in the laboratory, eating sushi or participating in karaoke, I encountered a paper that fascinated me; ‘Combining 3D printing and liquid handling to produce user-friendly reactionware for chemical synthesis and purification’ was the title of the article.1 The group of Lee Cronin at The University of Glasgow described the fabrication of a multi-chamber reaction vessel, with each region having different catalysts printed onto its surface – in this case Montmorillonite K10 and Pd/C (Figure 1). Building up around the loaded base layer and subsequent sealing of the entire unit allowed, after 90 degree rotations, the synthesis of 3a and 3b (Figure 3) via an initial acid-catalysed Diels-Alder cyclisation, imine formation and subsequent reduction over palladium on carbon with triethylsilane.


Figure 1: Fabrication of Reaction Vessel1

A schematic of the reaction vessel can be seen in Figures 2 & 3. The first split chamber contains solutions of the initial reactants. When rotated by 90o, the two solutions combine in a second chamber that has been layered with Montmorillonite K10. Once the first reaction is complete (5 h), the box is rotated again by 90o in order to initiate imine formation. A third rotation by 90o passes the solution over a printed surface of palladium on carbon in the presence of triethylsilane, which acts to reduce the imine to the corresponding amine. The crude mixture is finally passed through a silica plug to give the desired final products in yields similar to those utilising traditional glassware (32% vs 40% for 3a, 30% vs 38% for 3b).


Figure 2: Schematic of Reaction Vessel1


Figure 3: Rotation and Reaction in Separated Chambers1


So, with the above in mind, do we really need lab-based synthetic chemists? Probably – the current range of reactions applicable to this technology is rather limited to robust and well established chemistry; mixtures that are happy to be left under atmospheric conditions, in the presence of water and without proper temperature regulation. However, although there are currently quite a few limitations, I do feel that perhaps after optimisation by a trained scientist, people unfamiliar with advanced synthesis techniques or liquid handling will be able to synthesise pure compounds (medicinally relevant or not) by picking up a box from the shelf and following instructions like one might do with piece of flat-packed furniture from one of the world’s favourite Swedish stores – surely nothing can go wrong with that?


Blog written by: Mark Honey



  1. P.J Kitson,   M.D. Symes,   V. Dragone and  L. Cronin  Chem. Sci., 2013,4, 3099-3103





Green and Sustainable Medicinal Chemistry – 25 years later

What is Green Chemistry?

In short, Green Chemistry aims to prevent pollution through waste minimisation and by avoiding toxic and hazardous substances in the production and application of chemical products.  This is achieved by substitution of undesirable chemical products and processes by cleaner, safer and environmentally friendlier alternatives.1

In the 1990s the 12 Principles of Green Chemistry were established (Figure 1).


Figure 1: 12 Principles of Green Chemistry.  Image taken directly from source.1


Green Chemistry Metrics and Tools to assist Medicinal Chemists

Atom economy (AE)



Environmental factor (E factor)

The E-factor is the amount of waste (kg) produced when 1 kg of desired product is made, taking into account all of the auxiliary components – yield, reagents, waste solvents, waste from chemicals used in work-up and fuel (although difficult to quantify) and can be applied to a multistep process.1

Solvent Selection guides

Solvent selection guides exist that give information about the hazards of particular solvents (Table 1).2  Solvents represent at least half of the material used in the synthesis of pharmaceuticals and a significant amount of the waste per kg of desired compound.2

Recently, solvents have been ranked as follows:2

– Recommended (or preferred): solvents to be tested first in a screening exercise, if of course there is no chemical incompatibility in the process conditions.

– Problematic: these solvents can be used in the lab or in the Kilolab, but their implementation in the pilot plant or at the production scale will require specific measures, or significant energy consumption.

Hazardous: the constraints on scale-up are very strong. The substitution of these solvents during process development is a priority.

Highly hazardous: solvents to be avoided, even in the laboratory.



Table 1: CHEM21 solvent guides (both taken from directly from source)2

Reagent guides

Members of the ACS GCI Pharmaceutical Roundtable have access to a Reagent guide that’s aim is to encourage chemists to choose ‘greener’ reaction conditions.  At the moment I have not come across a similar guide for non-members.  For the time being it is up to the individual to search in Reaxys or Scifinder, look at reaction conditions and choose greener alternatives.

Green Chemistry and Pharma

Roger Sheldon’s E(fficiency) factor highlighted that Pharma in particular produces vast amounts of waste per kg of desired product (Table 2).3


Table 2:  The E factor (taken directly from source)3

However, it is important to note that the E factor does not take into account that the implicit molecular complexity of pharmaceuticals is twinned with limited engineering flexibility of reaction set-up.  This puts a significant responsibility for synthetic efficiency directly upon the medicinal chemist compared to those producing Bulk chemicals.  It also does not recognise that some waste is more hazardous than other waste products.4

Over the past two decades the Pharma industry has made great strides in incorporating Green Chemistry and engineering philosophies, especially into process development (read on for highlights).1

Advances in In Silico drug design and increased understanding of physicochemical properties (e.g. Lipinkski’s Rule of 5) has undoubtedly reduced waste through better and more targeted design.4  Many companies and academic institutions (including the SDDC) are documenting experiments in electronic lab notebooks (ELN) rather than using paper lab books thus reducing waste.

The ACS GCI Pharmaceutical Roundtable (12 globally leading pharmaceutical companies and 3 associate members) was established in 2005 specifically to encourage the integration of green chemistry and green engineering in the pharmaceutical industry.

Process Chemistry highlights

MSD and Codexis’ collaboration on the greener synthesis of Sitagliptin increased the overall yield by 50% and reduced the amount of waste by 80%.  This was achieved by discovering that the amino group of a key enamine intermediate did not need to be protected prior to enantioselective hydrogenation (pathway b).5  Codexis then went one step further and through directed evolution and biocatalysis were able to streamline the process.  High-pressure hydrogenation, rhodium catalyst, and the chiral purification steps were eliminated, providing a 13% increase in overall yield to 87% (pathway c).6


Scheme 1:  Greener synthesis of Sitagliptin (image taken from source)7

The telescoping synthesis of Imatinib (Gleevec) by the Ley group furnished pure product in 32% overall yield and > 95% purity (Scheme 2).  The apparatus engineered employed solid supported scavengers packed into a series of columns to minimise the waste associated with work-ups and purifications between steps.  In-situ reaction monitoring and infrequent handling of potentially hazardous intermediates was also advantageous.8


Scheme 2:  Ley’s greener synthesis of Gleevec (image taken from source)8

The Boots synthesis of Ibuprofen is a classic in Green Chemistry.  The original synthesis (Scheme 3) devised in the 1960s produced a vast amount of waste as a consequence of poor AE.


Scheme 3: 1960s Boots synthesis of Ibuprofen

In 1991 a three-step synthesis was devised by Boots-Hoechst-Celanese (BHC) that had high AE thus eliminating most of the waste by products (Scheme 4).  Hydrofluoric acid, Raney nickel and palladium catalysts were recycled, again reducing waste and making the process even more efficient.


Scheme 4:  1991 BHC greener synthesis of Ibuprofen

Recent ‘Green’ reaction highlights

Looking through the ‘most read’ articles of high impact journals there are an increasing number of Green and Sustainable chemistries reported.  Below I have picked some interesting examples of ‘greener’ reactions that caught my eye and may be attractive to other medicinal chemists.

Li’s photoinduced trifluoromethylation of inactivated arenes avoids the use of expensive metal and toxic metal catalysts (Figure 2)9.  The same group also reported a photoinduced metal-free aromatic Finklestein reaction and Sonogashira coupling.11

Figure 2:  Li et al Photoinduced trifluoromethylation of inactivated arenes (image taken directly from source)9

The Stahl group showed that a copper(I) salt and TEMPO (2,2,6,6-tetramethylpiperidinyl-N-oxyl) selectively oxidise a range of primary alcohols to aldehydes at room temperature with ambient air as the oxidant (Figure 3).12


Figure 3:  Stahl’s air oxidation of alcohols (image taken directly from source)12

Mechanistic studies encouraged the same group to develop a new catalyst system that exhibits broader scope and efficiently oxidizes both primary and secondary alcohols (Figure 4).12


Figure 4:  Stahl’s air oxidation of alcohols (image taken directly from source)12

The main advantages of this reaction are the lack of stoichiometric reagents used (other than oxygen) which greatly simplifies product isolation and reduces waste. Also chlorinated solvents, which are commonly needed with other classes of oxidation reactions, are not required.12

During my project I have had some experience in using T3P® in amide couplings.  In general its use has shortened my reaction times and improved yields over more conventional coupling reagents.  The main advantages reported for T3P® are lower levels of epimerisation, easy work-up as only water-soluble by-products are formed (Scheme 5).13  T3P® is also less hazardous compared to some conventional coupling reagents such as HOBt (now classed as explosive).13


Scheme 5:  T3P® amide coupling (image taken from source)13

T3P® has also been used in the synthesis of Denagliptin (Scheme 6), initially for amide bond formation and then subsequent dehydration of the primary amide to form the nitrile.13  Thus avoiding the use of hazardous reagents such as phosphorus oxychloride or thionyl chloride.


Scheme 6:  T3P® amide dehydration (image taken from source)13


Green Chemistry begins with good synthetic route design by the medicinal chemist.  There are now a number of tools and metrics in place to help medicinal chemists to choose the most attractive route both in terms of reaction efficiency and safety.  It is obvious that reducing waste at the source (the lab) will minimise the cost of its treatment and will strengthen economic competitiveness through more efficient use of raw materials.

The increased adoption and publication of ‘greener’ reactions will populate databases such as Reaxys which in turn will encourage chemists to use ‘greener’ reagents and procedures for their own safety.  Ultimately, it is up to the individual chemist to find and use ‘greener’ reactions and it is important that these ‘greener’ reactions are just as good as conventional reactions in terms of reaction efficiency.

It will be interesting to note how future investments and government policy on sustainable and green processes will be shaped by the falling price of fossil fuel derived feedstocks, as a result of lifting sanctions on Iran and the current Shale Gas revolution.

Hopefully, one day we will move towards a greener circular economy rather than the traditional ‘take-make-use-dispose’ economy.  It is promising (at least for the time-being for a Brit!) that Principle 2 (Figure 1) and this green philosophy that encapsulates it, forms the basis of the European Commission’s “Roadmap to a resource efficient Europe”.1


Blog written by: Scott Henderson


  1. A. Sheldon. Green Chem., 2016, 18, 3180.
  2. Prat et al. Green Chem., 2016, 18, 288.
  3. A. Sheldon. Chem. Ind., 1992, 903.
  4. L. Tucker. Organic Process Research & Development 2006, 10, 315.
  5. B. Hansen et al J. Am. Chem. Soc. 2009, 131, 8798.
  6. https://www.organicdivision.org/ama/orig/Fellowship/2013_2014_Awardees/Essays/Payne.pdf
  7. https://en.wikipedia.org/wiki/Process_chemistry
  8. G. Newman and K.F. Jensen. Green Chem., 2013, 15, 1456.
  9. Li et al J. Am. Chem. Soc. 2016, 138, 5809.
  10. Li et al J. Am. Chem. Soc., 2015, 137, 8328.
  11. Li et al. Nature Communications, 2015, 6, 6526.
  12. S. Stahl and B. L. Ryland. Angew. Chem. Int. Ed. 2014, 53, 8824.
  13. http://www.euticals.com/attachments/article/20/EUTICALS_T3P.pdf



Big Pharma and their adoption of Orphan Drug Research

A rare disease/disorder is defined as such when it affects fewer than 200,000 (USA) or fewer than 2000 (Europe) of the population at any given time. To date, over 7000 rare diseases have been identified, affecting more than 350 million people globally. In the EU, as many as 30 million people may be affected, with the same number affected in the USA. Fifty percent of those affected are children, with approximately 52 million of these children not living to see their 5th birthday.1 Considering that only 5% of rare diseases have an FDA approved drug, how much research is being carried out by Pharmaceutical companies towards orphan diseases?

Drug discovery is an expensive and time-consuming business, with strict regulatory standards and high attrition rates. According to the Tufts Center for the Study of Drug Development, as of 2014 the cost of developing a single drug stood at approximately $2.9 billion.2 Traditionally, big Pharma focused on developing drugs aimed at “common diseases” with a large patient population to maximize the possibility of recovering research and development costs, with rare diseases pushed aside because they provided little financial incentive. These rare diseases were said to be “orphaned”, and can also include common diseases that have been ignored because they are far more prevalent in developing countries than in the developed world.

In 1983, Congress passed the Orphan Drug Act which provided manufacturers with three attractive primary incentives.

  • Federal funding of grants and contracts to perform clinical trials of orphan products
  • Tax credit of 50% of clinical testing costs
  • An exclusive right to market the orphan drug for 7 years from the date of marketing approval

The Food and Drug Administration commissioned the Office of Orphan Products Development (OOPD) to dedicate its mission to promoting the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. In fulfilling that task, the OOPD interacts with the medical and research communities, professional organizations, academia, governmental agencies, and the pharmaceutical industry, as well as rare disease groups. The OOPD also administers the Orphan Products Grants Program which provides funding for clinical research that tests the safety and efficacy of drugs, biologics, medical devices and medical foods in rare diseases or conditions.3 The program has successfully enabled the development and marketing of more than 400 drugs and biologic products for rare diseases since 1983. In contrast, the decade prior to 1983 saw fewer than ten such products come to market.

So, with this in mind, how has research into orphan drugs progressed?

One biotech company stands out. Genzyme was founded in 1981, producing modified enzymes to test in clinical trials. In 1991, Genzyme won FDA approval for Ceredase for the treatment of Gaucher’s disease, the success of which allowed Genzyme to concentrate research into recombinant human enzymes to treat enzyme deficient conditions. To overcome supply constraints, Cerezyme quickly replaced Ceredase a few years later, and in 2010 Genzyme became the fourth largest American biopharmaceutical company with a revenue of $4 billion. In 2011 Sanofi acquired Genzyme for approximately $20 billion making Genzyme its global center for excellence in rare diseases.

The marriage between Shire and Baxalta early this year has made them the Global leaders in rare diseases, creating the number one rare diseases platform in revenue and pipeline depth.4 The combined portfolio will have over 50 programs that address rare diseases. Shire anticipates more than thirty recent and planned product launches from the combined pipeline, contributing approximately $5 billion in annual revenues by 2020.

Big pharma now wanted a slice of the pie, and drug research into rare diseases was not exclusive to Biotechs.

In 2014 Pfizer joined with the Global Medical Excellence Cluster (GMEC), a group of six leading UK universities to form a Rare Disease Consortium, focusing on exploring the human genome to treat hematologic, neuromuscular and pulmonary rare diseases.5 Professor Michael Linden (Kings College London) joined Pfizers newly formed Genetic Medicine Institute in 2015 to evaluate the viability of producing effective, clinical grade gene therapy viruses.6

In 2015, Dr. Mark Fishman, President of the Novartis Institutes for BioMedical Research (NIBR) stated that “Our focus on rare diseases flows from our desire to help patients underserved by today’s medicines.” Novartis scientists have investigated treatments for more than 40 rare diseases, with the US Food and Drug Administration granting Novartis dozens of “orphan drug” designations. They also have more than 15 medicines approved for these conditions.7

In 2015 Roche bought the French pharma company Trophos and its lead drug for the rare neuromuscular disease spinal muscular atrophy (SMA) for €470 million.8 They have also taken on board the genomics firm Foundation Medicine  as well as a collaboration with genetic testing specialist 23andMe in Parkinson’s disease.9

GSK has established its own research unit exclusively devoted to seeking cures for rare diseases. GSKs partnership with Ospedale San Raffaele Telethon Institute for Gene Therapy and Fondazione Telethon (Telethon) has resulted in a recent European approval for Strimvelis, the first ex-vivo stem cell gene therapy to treat patients with the very rare disease, ADA-SCID.10

In April this year, Astra Zeneca announced that along with MedImmune, a genomics initiative has been launched to transform drug discovery and development across its entire research and development pipeline. AstraZeneca has partnered with research institutions including the Wellcome Trust Sanger Institute (UK), Human Longevity Inc. (US), and The Institute for Molecular Medicine (Finland) in the hope to unearth rare genetic sequences that are associated with disease and with responses to treatment.11

The emergence of patient advocacy groups has improved the understanding of how debilitating these diseases can be, with the non-profit organisation Global Genes® being one of the leading rare disease patient advocacy organizations in the world, promoting the needs of the rare disease community.1 Passing of the FDA’s Orphan Drug Act (and similar legislation in other countries) paved the way for biotech companies to carry out research into rare diseases, offering government incentives, shorter development timelines, and exclusive markets rights. Smaller clinical trials with a reduced patient pool and FDA fast track designation has led to an average time of 3.9 years from Phase II to launch, compared to 5.4 years for non-orphan drugs.12

Research into rare diseases by smaller companies was also made possible through funding by non-profit organisations such as the Cystic Fibrosis Foundation, operating like a venture capital firm. Big Pharma can support expensive research costs, especially when orphan drugs can bring in attractive revenues – Cerezyme has an annual treatment cost of  $300,000 per patient! According to the EvaluatePharma Orphan Drug Report 2015, worldwide sales are forecast at $178 billion by 2020, with the market growing by 11% each year.13

However, with more orphan drugs coming to market and the high costs per patient, will healthcare systems be able to continue to pay/subsidise for them?

Blog written by: Kamlesh Bala



  1. https://globalgenes.org
  2. http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study
  3. http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm
  4. https://www.shire.com/-/media/shire/shireglobal/shirecom/pdffiles/newsroom/2016/shire-to-combine-with-baxalta-pr-1-11-16-final.pdf?la=en
  5. http://www.pfizer.co.uk/content/rare-disease-consortium
  6. http://www.pfizer.co.uk/latest-news/2015-11-26-pfizer-hires-professor-michael-linden-lead-new-gene-therapy-research-centre
  7. https://www.novartis.com/stories/education-awareness/why-research-rare-diseases-matters
  8. http://www.roche.com/media/store/releases/med-cor-2015-01-16.htm
  9. http://www.roche.com/media/store/releases/med-cor-2015-01-12.htm
  10. http://www.gsk.com/en-gb/media/press-releases/2016/gsk-receives-positive-chmp-opinion-in-europe-for-strimvelis-the-first-gene-therapy-to-treat-very-rare-disease-ada-scid/
  11. https://www.astrazeneca.com/media-centre/press-releases/2016/AstraZeneca-launches-integrated-genomics-approach-to-transform-drug-discovery-and-development-22042016.html
  12. Meekings KN, Williams CSM, and Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discovery Today 2012; 17 (13/14):660-664.
  13. http://www.evaluategroup.com/public/reports/EvaluatePharma-Orphan-Drug-Report-2015.aspx



Manic Mice: A Model Of Bipolar Disorder



Bipolar disorder falls into a category of psychopathological conditions known as affective disorders. These conditions manifest themselves with  inappropriate and disproportionate exaggerations in mood state. Bipolar disorder itself consists of the swinging between major depressive and manic episodes. The manic episodes of bipolar disorder are the distinguishing factor that enable diagnosis. In many individuals however, manic episodes occur infrequently making diagnosis challenging. As a result, many patients are first diagnosed with depression and this leads to problems with treatment.

Circadian Rhythms and Bipolar Disorder

Patients with bipolar disorder suffer from disturbances in their circadian rhythms. In depressive episodes insomnia or hypersomnia are common factors, and in manic episodes there is a decreased “need for sleep”. The rhythm of sleep is also altered, in particular REM and slow wave stages of sleep. The normal rhythms of activity, hormonal secretions and appetite are also affected. Indeed the normalization of the sleep/wake cycle and exogenous zeitgebers plays an important part in treating many individuals suffering with the illness (Plante 2008). Recently SNPs (signal nucleotide polymorphisms) have been identified in genes that encode crucial components of our endogenous pacemakers associated with mood disorders (Benedetti 2008).  In addition to this, lithium and valproate, the most common mood stabilizing treatments both have known targets and effects in circadian rhythm biology. Lithium for example has been shown in many organisms to lengthen the circadian day and valproate to alter the expression of several circadian proteins.

Animal model of mania

CLOCK is a protein that is thought to play an important part in the molecular feedback mechanisms that make up our endogenous pacemaker. Described in this publication is a mouse model in which CLOCK was mutated to inhibit its interaction with BMAL1, its transcription regulatory complex partner. In the original paper several tests were employed to demonstrate that the mice exhibited different diagnostic criteria of mania (Roybal 2007).  One symptom of mania in humans is feelings of extreme euphoria. In mice this was examined by assessing helplessness in forced swim experiments. Positively the results indicated less helplessness in the mutants. Anxiety tests were also utilized and results were indicative of this second symptom of mania. The mutant mice also show a greater preference for rewarding stimuli, similar to the manic states in bipolar. This was examined by assessing the level of intracranial self-stimulation to the medial forebrain bundle. Finally disrupted circadian rhythms, hyperactivity and decreased sleep were also observed in the mice. Perhaps the most intriguing part of this model is the lithium sensitivity. Treatment with lithium was shown to ameliorate the mood-related effects of the mutation to wild type levels (in the helplessness and anxiety tests).

Evaluation (My Thoughts)

One major weakness in this model is the identification of CLOCK null mutant mice that exhibit normal circadian functioning (Jason 2006). This suggests that the CLOCK 19 mice dysfunction may result from new functions of the mutant CLOCK or a desynchronization of function or parallel function of CLOCK, with the mutations failing to completely inhibit CLOCKs function.

There is no evidence that suggests that mutations in the circadian system are required for the development of bipolar disorder in humans and therefore it could be argued that this model lacks any relevance to the human condition.

Bipolar disorder is more complex that the behavior displayed by these mice, which exhibit no cycling between mood states. These mice are at best a model of constant mania but their utility in predicting therapeutic efficacy remains unclear. At worst this model has no biological relevance for bipolar disorder. The observed influence of lithium in alleviating the effects of the mutation may be attributed to its intrinsic polypharmacology. In addition, in this study lithium was not able to restore all behavioral phenomena to wild type levels.

Despite these reservations it must be acknowledged that circadian rhythm dysfunction is an important factor in bipolar disorder and models that can be used in the development of drugs to “normalize” this are useful.


Blog written by: James Noble


  1.  Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, Campori E, 
Smeraldi E Am J Med Genet B Neuropsychiatr Genet, 2003123:23–26. 

  2. David T. Plante, John W. Winkelman, Sleep Disturbance in Bipolar Disorder: Therapeutic Implications Am J Psychiatry 2008; 165:830–843
  3.  Jason P. DeBruyne, Elizabeth Noton, Christopher M. Lambert, Elizabeth S. Maywood, David R. Weaver, Steven M. Reppert, A Clock Shock: Mouse CLOCK Is Not Required for Circadian Oscillator Function, Neuron, 2006, 50 (3), 465-477
  4. Kole Roybal, David Theobold, Ami Graham, Jennifer A. DiNieri, Scott J. Russo, Vaishnav Krishnan, Sumana Chakravarty, Joseph Peevey, Nathan Oehrlein, Shari Birnbaum, Martha H. Vitaterna, Paul Orsulak, Joseph S. Takahashi, Eric J. Nestler, William A. Carlezon, Jr, and Colleen A. McClung,Mania-like behavior induced by disruption of CLOCK, PNAS 2007, 104 (15), 6406-6411


The Sharpless Asymmetric Aminohydroxylation

Looking for methods to generate protected vicinal α-amino-β-alcohols, it is difficult to miss the work of Prof. Barry Sharpless who won the Nobel Prize in 2001 “for his work on chirally catalysed oxidation reactions”.1

In 1998 Sharpless and Reddy reported the osmium catalysed asymmetric aminohydroxylation (AA) reaction, which provided either (R)- or (S)-α-aryl-N-Cbz- or N-Boc- protected (R)- or (S)-α-amino-β-alcohols (R)- or (S)-(2) from styrenes (1) (Scheme 1).2  The enantioselectivities were generally excellent and a subsequent oxidation step yielded the corresponding α-arylglycine derivatives (R)- or (S)-(4).



Scheme 1: Asymmetric aminohydroxylation (AA) reaction of substituted styrenes by Sharpless and Reddy

It was observed that the regioselectivity was highly dependent on the nature of the styrene (1) as well as the choice of ligand, solvent, and ligand-solvent combination. Phthalazine ligands such as (DHQ)2PHAL or (DHQD)2PHAL in n-PrOH strongly favoured the benzylic amine (R)- or (S)-(2) over the benzylic alcohol (R)- or (S)-(3) regioisomer.

Investigating the extensions of this methodology I found a paper reporting the conversion of α,β-unsaturated esters to the corresponding β-hydroxyamides.As an example, Sharpless et al reported a synthesis of protected (2R,3S)-3-phenylisoserine (2R,3S)-(6), a precursor for the side chains of the anticancer drugs Taxol and Taxotere (Scheme 2).4


Scheme 2: Synthesis of (2R,3S)-(6)

Another important discovery was that anthraquinone ligands (DHQ)2AQN and (DHQD)2AQN imposed a regioselectivity pattern different from that seen with their more commonly used PHAL analogs (Scheme 3).5


Scheme 3: Regioselectivity of asymmetric aminohydroxylation (AA) reaction

Sharpless reported that the substrate orientation within the binding pockets of these two different ligand classes is obviously altered in such a way that opposite regioselection results, but remarkably, without affecting the sense or the degree of the enantiofacial selectivity. Most importantly the major product was obtained in the ration of at least 4:1 over unwanted regioisomer.

Sharpless demonstrated that versatility and great control in this reaction outweigh the toxicity and costs of the reagents. Although osmium tetroxide is well known for causing severe damage to the eyes, potassium osmate is a commercially available stable solid, which is a lot easier and safer to handle than osmium tetroxide. While catalyst and chiral ligand cost around £100 per gram, the loading is minimal (~ 5 mol%).

This quickly has become one of my favourite reactions due to its reliability and practicality. However I do still remember the first time I had to use osmium tetroxide reagent as an undergraduate student, and my boss telling me: “Stop messing around, just do the reaction with your eyes closed!” Still not sure if he was joking…

Blog written by: Victor Zdorichenko 


  1. Nobelprize.org. Nobel Media AB 2014. <http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2001/>
  2. Reddy, K. L.; Sharpless, K. B.; J. Am. Chem. Soc. 1998, 120, 1207–1217
  3. Demko, Z. P.; Bartsch, M.; Sharpless, K. B.; Org. Lett. 2000, 2, 2221–2223
  4. Bruncko, M.; Schlingloff, G.; Sharpless, K. B.; Angew. Chem. Int. Ed. Engl. 1997, 36, 1483–1486
  5. Tao, B.; Schlingloff, G.; Sharpless, K. B.; Tetrahedron Lett. 199839, 2507-2510