February 22nd 2010

"Engineering Medicines - Progress towards magic bullets for                                       curing diseases"

                               given by Dr Alan Haines
School of Chemical Sciences and Pharmacy, UEA and an NES                                       Member

The major purpose of this talk was to show how the creation of modern medicines (drugs) is often - but not always - the result of similar processes that are followed by engineers in their quest for solutions to problems in their own particular field, that is firstly the recognition and understanding of a problem requiring a solution, secondly the design of a possible solution within recognised constraints, and thirdly the production to that design of the object which will provide the required solution.

This success of this type of approach in the medical field is relatively recent -essentially over the last 30 to 40 years - and has had to await developments in many areas of biology, chemistry, physics and medicine. Foremost amongst these are:

    i)     a fuller understanding of the underlying biochemistry of human, viral and bacterial organisms
    ii)    development of methods for the isolation, purification and crystallisation of proteins (specifically enzymes and receptors)
    iii)   rapid methods for determination of protein structure based on X ray crystallography, which in turn has depended on the             development of faster computers and improved software
    iv)   improvement of methods for the chemical synthesis of complex molecules as potential drug candidates
    v)    the development of methods for the rapid determination in the laboratory of the efficacy of potential drug candidates.

The history of drug development, however, has not provided examples of such a logical approach but has been one of serendipity - chance discovery exploited by the prepared mind, an important facet for the success of scientific investigation pointed out by Louis Pasteur in the 1800s. Therefore, a full understanding of where medicinal chemistry is today requires that we look back and understand this type of chance discovery process and also understand how we have learnt from folk medicine which plants may contain important chemicals that has led to their use, even since primitive times, to alleviate certain symptoms or even cure diseases.

With these factors in mind, the talk evolves into a consideration of drug discovery and development from early days to the present and in order to provide a useful background for the general audience it is necessary to introduce a consideration of natural responses of animals to infection through their immune system (antibodies and killer T-cells) before moving onto the design by chemists/biochemists of medicines to combat specific diseases.
A fundamental point to be understood by anyone wishing to gain knowledge of medicinal chemistry is the vital importance of the phenomenon of molecular recognition which is best explained by the "lock and key" analogy. A suitable fit between an enzyme (catalyst) and its substrate is a pre-requirement for chemical change to occur, as it is in the interaction between a receptor and associated messenger molecule (e.g. adrenaline acting on the heart to increase blood supply). The interaction between an antibody and an invading organism (e.g. a virus) also requires a "molecular fit" as does the successful attack of an organism such as a virus on its potential host. The success of our antibodies in dealing with many types of infection by foreign invaders is remarkable but on rare occasions antibodies may fail to recognise "self" cells and by attacking them lead to autoimmune diseases such as type 1 diabetes and rheumatoid arthritis.
It is helpful to realise the size of our invading organisms. A typical bacterium is 2-3 x 10-3 mm = 2-3 x 10-6 m = 2000-3000 nm long and a typical virus is roughly one-tenth that size at 1/10000 of a mm = 100 nm. A bacterium often has a flagellum for propulsion and most importantly a cell wall composed of a cross-linked polymer made of carbohydrate and amino acid molecules, a feature absent from human cells and which is a key factor in understanding the success of penicillins in treating disease. A virus can have remarkable symmetry (e.g. exist in the form of an icosahedron {20 sides} or have a helical structure) and in the case of the HIV it has projections on its surface formed from glycoproteins which are essential for its "docking" procedure when attacking a host.

There is clearly a need to turn to medicines when the immune system fails or needs help and aspirin (a product of the 19th century and related to the important chemicals giving willow bark its value as an early medicine) has a new found importance as an anti-clotting agent. Vaccination, developed from the important observations of Jenner (1778) on the immunity towards smallpox of milkmaids who had been in contact with cow pox, forms a vital part of our armoury against viral diseases such as polio and diseases such as typhoid.

Paul Ehrlich (Nobel Prize 1908) is the person who can be regarded as initiating the modern idea of chemotherapy with his concept of the 'magic bullet' - a chemical that would show selective toxicity towards an invading organism without harming the host. With his remarkable foresight he developed the arsenic based drug Salvarsan which was a key treatment of syphilis until the 1940s until superceded by penicillins.

The story of the chance discovery of penicillin by Alexander Fleming is well documented - a good example of chance favouring the prepared mind - but although the discovery was made in 1928, it was more than 10 years, and finally with the help of the Americans, before sufficient quantities of material of good purity was available.
Thus, the discovery of the sulphonamides in 1935 by the Essex based firm of May & Baker preceded the general availability of the wonder drug penicillin and it marks a milestone in the development of modern chemotherapy. A key point to realise, is that before this time there was little that the medical profession could offer in the treatment of diseases such as pneumonia and it was instrumental in helping to cure Winston Churchill when he contracted pneumonia during a visit to North Africa in December 1943. Its mode of action, as an antagonist of p-aminobenzoic acid (an essential requirement for the growth of bacteria) was recognized and after many trial compounds they came up with the famous M&B 693 (sulphapyridine).
The outstanding ability of the penicllins to counteract a variety of bacteria is a result of bacteria having the fundamental requirement to form a rigid cell wall comprising a cross-linked polymer of sugars and amino acids, a structure which does not occur in cells of the host. The penicillins interfere with the enzymically catalysed cross-linking step which is performed on the precursor linear polymer. Although resistance has developed to many members of this class of drugs (? lactams), chemists have been able to modify their basic structure or isolate new representatives (cephalosporins) which regain ascendancy until new resistance develops.

An important anti-cancer drug is cis-platin, resulting again from a serendipitous discovery, and in various modifications it has proved a valuable drug in this area of chemotherapy. Its mode of action stems from its ability to interact with DNA chains during the unwinding and replication process required during cell division, thus preventing cell growth.
The latter part of the talk focussed on the more modern era of drug development, alluded to both in its title and in the introduction, whereby the design and syntheses of drugs have been undertaken for specific purposes and with an understanding of the underlying biochemistry, to counteract particular types of health problems. An outstanding example is the development of the so-called beta-blockers which hinder access of the natural messenger adrenaline to the receptors on the heart and which activates the latter for increased output in times of stress or shock (the fight or flight response). One such example is the adrenaline antagonist Propranolol.
The final part of the talk concerned viruses, the mode of infection, reproduction, and methods for combating them. In particular HIV and swine flu virus were highlighted. HIV is an RNA virus (the genetic information is held in the form of RNA rather than DNA) and requires reverse transcription of the RNA into DNA by the enzyme reverse transcriptase before the machinery of the host cell can be commanded to make the components of the invader, firstly in the form of a long protein which is then cleaved by a protease enzyme to yield the individual smaller proteins. Attack on the virus is usually achieved with inhibitors of both these enzymes, AZT being a drug acting on reverse transcriptase. The development of inhibitors of the protease enzyme depended on an X-ray crystallographic determination of the enzyme’s structure, and particularly of its active site. With this information compounds could be synthesised which would bind specifically and tightly to this site, and the drug Saquinavir was one of the first such compounds to be prepared.
The recent scare over the emergence of swine flu, with the fear that a pandemic disease might ensue, led to considerable focus by the pharmaceutical industry on the production of suitable anti viral drugs and very large number of doses of the drug Tamiflu were produced by Roche, as were also of the related drug Relenza by GSK. Both of these compounds are classed as neuraminidase inhibitors; the release of a newly "budded" virus depends critically on the cleavage of a bond between N acetylneuraminic acid (sialic acid) and the infected host cell catalysed by the enzyme neuraminidase which is incorporated in the coat of the emerging virus. Sialic acid residues appear ubiquitously on many of our cells and are points of anchor for the budded virus; without bond cleavage the virus cannot escape and become a new infective organism. Both Tamiflu and Relenza are molecules tailored to resemble sialic acid and are able to occupy preferentially the catalytic site of the enzyme thus preventing it functioning on its normal substrate.
A molecular model of Tamiflu gives an idea of its overall topography, and apart from having a "lock/key" relationship with its target enzyme the drug must also form strong intermolecular bonds within the active site.
The talk ended with Alan posing the question "Does the future development of drugs depend on engineering medicines - or does serendipity still play a part"? The fact that chance and a prepared mind will still play an important part in the quest for drugs of the future is indicated by the fact that Pfizer produced Sildenafil as a compound designed to dilate blood vessels to treat angina and hypertension; it certainly does dilate blood vessels but not quite in the manner for which it was designed - it is better known today as the drug Viagra!

Alan rounded his talk off with the suggestion that some of the audience might wish to follow up some of the areas covered and medicinal chemistry in general by suitable reading, and attention was drawn to two excellent books by Professor John Mann the details of which are given below.

Suggested further reading:

1. 'The Elusive Magic Bullet - The Search for the Perfect Drug' - John Mann - Oxford University Press -1999. ISBN 0-19-850093-9 (Hbk) or ISBN 0-19-850092-0 (Pbk)

2. 'Murder, Magic, and Medicine' - John Mann - Oxford University Press - 1999. or ISBN 0-19-855854-6 (Pbk)