Retropharmacology: From Drug to lead

Drug discovery is a lengthy, high-risk, and costly endeavor; many strategies are available to accelerate the development process to provide high-quality drug candidates. The diminished interest in Natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry. However, these new technologies promise to fill the drug development pipeline with small-molecule candidates is unfulfilled. Learning from the past with the appropriate strategy for the future is essential to make a significant difference.

Valerian has been used as a medicinal herb science at least the time of ancient Greece and Rome as a sedative, migraine treatment, pain reliever, insomnia, and other disorders as an alternative to benzodiazepine drugs.

Valerenic acid, a significant constituent of common valerian, is a potent modulator of  GABA-A receptors. In order to develop a broader understanding of structural requirements for GABA-A modulatory activity of valerenic acid. Kopp et al. (chem med chem) synthesized several analogs and found that some of the derivatives such as tetrazole (pic) are proved to be the most potent allosteric potentiators of GABA-induced ion currents, and its activity exceeds the activity of valerenic acid and Diazepam.

This reverse pharmacology approach, relates to reversing the routine ‘laboratory-to-clinic’ progress to ‘clinics-to-laboratories’ (inspired by traditional medicine), can offer a smart strategy for new drug candidates.

The rise biopharmaceuticals

The movement of big pharma into biologics  (biopharmaceuticals) understandably has a direct effect on the pharmaceutical landscape. Companies show a diminishing portfolio revenue from small molecule drugs, primarily because of patent expiration on blockbuster drugs (small molecules) and the reallocation of industry resources towards biologics.

Biologics represent one of the most promising frontiers in pharmacotherapy; USFDA approved more biologics in 2009, the figure includes 19 new molecular entities (NMEs) and six novel biologics. In 2008 FDA approved 21 NMEs and three novel biologics. A substantial improvement in biologics approvals in 2009. (fig.1, Nature Medicine, 139, 16, 2010). Moreover, it is expected to take over from small molecule field in the coming years (fig 2, Nature reviews / drug discovery). However, their cost can be substantial, reaching $200,000 or more annually for treatment (Cerezyme), and the large molecules drugs are administered via injection – a less popular option with patients.

Biologics are gradually going to replace the traditional approach to drug design. Students need to understand industries changing needs if they plan on carriers in this area.

Kill the Bugs, Selectively

“Today, we have tuberculosis drugs you have to take for nine months, why can’t we find one that works in three days” - Bill Gates. 

Tuberculosis (TB) is a chronic contagious disease caused by  Mycobacterium tuberculosis (M.tb), one of the leading causes of death worldwide. The WHO estimates about one-third of the world’s population is infected with M.tb, 10% of those infected will progress to active TB disease during their lifetime. The tuberculosis pandemic has been declared a global health emergency as the growing resistance of M.tb to Antibiotics coincides with the spread of risk factors such as HIV/AIDS and diabetes. TB is a complex disease. The current TB drug regimen, a product of scientific advances of the 1960s, requires six to nine months of treatment for active, drug-susceptible TB. Unfortunately, many patients do not or cannot complete this treatment. Poor adherence and prescribing practices have led to the emergence of multi- and extensively drug-resistant strains of TB (MDR-TB and XDR-TB) that increasingly defy current medicines and spread throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics.

 

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome. A team of scientists led by researchers from Weill Cornell Medical College  has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes. These compounds were showing no apparent toxicity to mammalian cells. The oxathiazolone compounds are the first example of an anti-tubercular agent that inhibits protein breakdown. The ability of brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy. These  findings  may lead to drugs that destroy TB in the dormant stage of the lifecycle.

Tamiflu

A new strain of swine flu, an H1N1influenza virus, is spreading around the globe. The WHO has declared the novel H1N1 influenza virus (swine flu - 2009) outbreak a global pandemic - First Phase 6 Influenza pandemic since 1968.

(_)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used to treat both type A and type B human influenza. Currently, it is the most effective drug for the treatment of Influenza. However, the unmet supply of this drug demands urgent solutions. The manufacture of Tamiflu by Roche Company utilizing naturally occurring shikimic acid as the starting material. Getting stable quality of pure shikimic acid may be problematic. 

The Tamiflu supply problem has piqued the attention of academic chemists. Several labs have already reported new methods for making Tamiflu without shikimic acid. However, it is challenging to evaluate academic syntheses from the standpoint of potential as a manufacturing process because they have not been developed for large-scale operation. Considering the amount of Tamiflu required worldwide, there is an urgent demand to improve the production process.

Here is the retrosynthetic analysis for the shortcut synthesis of Tamiflu. This synthesis initiated by oxa-Michael addition of alcohol to acrolin, which was reported by Zhang et al,

Going Right-handed

Why are we made of only right-handed sugars? That has long been one of the biggest puzzles in understanding how life began, and this origin of homochirality in sugars and amino acids has been intrigued researchers for decades. So for convincing theory and experiment on the origin of homochirality are still lacking.

Armando Co´rdova and coworkers at Stockholm University, Sweden, used amino acid as a catalyst for the formation of hexoses sugars with >99 ee. Hexose’s have been suggested as building blocks of ancient RNA. It may be an example of the theoretical basis for the evolution of sugars' homochirality (right-handed configuration) in the prebiotic world.

Andrew Pohorille and Chenyu Wei at NASA Ames Research Center found that ribose permeates membranes an order of magnitude faster than its diastereomers. On this basis, it was hypothesized that differences in membrane permeability to aldopentoses provide a basis for preferential delivery of ribose to primitive cells for subsequent selective incorporation into nucleotides and their polymers.

D ribose (right-handed sugar) polynucleotide tends to form right-handed helices; what is the neutral macroscopic cause that gave rise to the preference of both right-handed helical nucleic acids and proteins on Earth? 

Y J He et al suggested that a net natural chiral right-handed helical force field, produced by the Earth’s orbital chirality (EOC) could affect the stability of molecule helical enantiomers and make the right-handed helical enantiomers more stable than their left-handed enantiomers. So, terrestrial living systems must select right-handed nucleic acids based on D-sugars and right-handed proteins based on L-amino acids.

This homochirality can be observed on the macroscopic scale, for example, the helical chirality of snail shells (preferred right-handed) and the helical winding of some kind of plants. 

Maybe a complete understanding of life and its evolution will never be possible. However, this will not certainly stop scientists from seeking the secret of the origin of life. Whitesides recently expressed the current state of understanding of the origin of life in frank words,

"Most chemists believe, as do I, that life emerged spontaneously from mixtures of molecules in the prebiotic Earth. How? I have no idea. Perhaps it was by the spontaneous emergence of “simple” autocatalytic cycles and then by their combination. On the basis of all the chemistry that I know, it seems to me astonishingly improbable." 

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