Medicinal compounds

John Mann, Queen’s University Belfast, takes a look at drugs on the market.
In this issue: bird flu – how can chemistry help?

Will there, or won’t there be an influenza pandemic? The messages emanating from Government and the media are either wrong or at best ill-informed. The facts are simple. Since 1997 a new strain of fowl influenza (H5N 1), has decimated the chicken flocks of Hong Kong, Thailand, Vietnam, and many other countries in South East Asia. Those birds not killed by the virus have been slaughtered to prevent spread of the disease. More worryingly, at least 100 people have been infected by this avian virus and about half this number have died. But the good news is that, thus far, there is no evidence for human to human transmission of this viral strain. However, it may be only a matter of time before the virus mutates to produce a new variant that can pass from human to human and then we really are in trouble. 

So how can chemistry help?   

The influenza A virus is spherical in shape with a diameter of about 10Onm. Its cell surface comprises two types of glycoproteins: haemagglutin (HA), of which there are at least 15 discrete sub-types; and neuraminidase (NA) of which there are at least nine sub-types. The various combinations of theses serotypes provide the ‘antigenic signature’ of the strain of virus. For example, the strain responsible for the 1918 flu pandemic, which killed at least 20 million people, was H1N1, while the Asian flu epidemic of 1957 was H2N2, and the epidemic of 1968 (Hong Kong flu) was H3N2. So H5N1 would be a new strain for humans. 

Governments can prepare for flu epidemics in two ways. They can stockpile large batches of vaccines, but these will only be effective if the infecting serotype for humans has been identified, and this is clearly not yet the case for bird flu; or they can prepare large quantities of the new flu drugs – for example, the neuraminidase inhibitors Relenza and Tamiflu. 

So how do these work? The neuraminidase glycoprotein is anchored to the lipid bilayer of the viral cell membrane by hydrophobic amino acids, and the drugs appear to work primarily by destroying neuraminic acid (sialic acid) receptors on the surface of the viruses and also on the host cells from which the newly formed viruses are emerging. This has the dual effect of allowing the viruses to escape from the host cells and also prevents them from clumping together. Once the three dimensional structure of flu neuraminidase had been determined using X-ray crystallography by the Australian scientists Colman and Laver in 1983, work began on the design of small molecules that would interact with the enzyme and cause inhibition. Mark von Itzstein and his group at Monash University in Melbourne were first to design potent inhibitors of the enzyme. Subsequent optimisation of compound activity was done in the UK by GSK and in the US by Gilhead labs and Hoffman LaRoche, with the ultimate production of the drugs Relenza and Tamiflu respectively. These drugs reduce the symptoms of flu if administered within two days of the first symptoms appearing and will then reduce the duration of morbidity by one and a half to three days. Relenza has to be administered as an inhaled powder while Tamiflu can be taken orally, so not surprisingly the UK Government has opted for the production of a huge batch of Tamiflu. 

Only time will tell whether this present strain of bird flu will mutate into a form that can be transmitted from human to human, but it should be possible to prevent a pandemic by the prompt use of these new neuraminidase inhibitors in conjunction with the arsenal of antibiotics that are available to treat the associated bacterial infections. Neither of these options was available during the great flu pandemic of 1918.