Chemistry vs viruses

We are going to spend most of this chapter discussing two medical developments, both battles pitting chemists against viruses: one is partly won, and one has fortunately not yet been fought. Like cancer, viruses are an insidious menace because they subvert the body’s own biochemical machinery to cause harm, but since the middle of the last century, with antibiotics being used to treat bacterial infections, the threat from infectious disease seemed to be in retreat. So when AIDS (acquired immune deficiency syndrome) fi rst came into the news in the 1980s, medics struggled to explain the mysterious deaths from normally harmless diseases after the patient’s immune system had been weakened and eventually destroyed. But the cause was soon identifi ed by biologists as a new virus, HIV (human immunodeficiency virus), and antiviral drugs, notably AZT, were used with some success. These drugs imitate natural nucleosides (AZT imitates deoxythymidine) and inhibit the virus from copying its RNA into DNA inside human cells by inhibiting the reverse trans criptase enzyme. As is often the problem with antiviral (and anticancer) chemotherapy, the drugs also inhibit the normal function of essential human enzymes and are very toxic. But biologists discovered an alternative point of attack. An enzyme unique to the virus cuts up long proteins into small pieces essential for the formation of new HIV particles. If this enzyme could be inhibited, no new viruses would be formed and neither should the inhibitor interfere with human biochemistry. Blocking HIV protease inhibitors means mimicking the proteins they slice up, but real pep tides are usually poor drugs because humans have their own peptidases which quickly cut up ingested proteins by hydrolysis of the amide link. The solution is to make a drug which looks like the peptide but can’t be hydrolysed because the C–N bond of the peptide has been replaced by a C–C bond (green parts of the structures below).

This stops the drug being hydrolysed, but the drug also has to stop the viral protein being hydrolysed. To get it to do this, medicinal chemists used another trick. Enzymes work by bind ing the transition state for a reaction, and while of course the chemists couldn’t make a transition state (it is by its nature unstable) they made a molecule with a sufficient resemblance to the tetrahedral intermediate for amide hydrolysis (black parts of molecules above) that the protease is tricked into taking it into its active site, where it blocks the protease’s function. The knowledge that only one of the two hydroxyl groups of the tetrahedral intermediate was needed was acquired from an X-ray crystal structure showing how the enzyme binds the substrate. Other structural information was also used to design the drugs: for example, HIV protease is a dimeric enzyme and experience with this class of protease suggested correctly that more or less symmetrically placed aromatic or heterocyclic rings would greatly improve binding. Two successful protease inhibitors are shown below, with the active site binding portion in brown and the heterocyclic binding portions in green.

These developments looked so promising that Merck set up a new research station at West Point, Pennsylvania, dedicated to this work. The biochemist in charge, Dr Irving Sigal, was one of the victims of the Lockerbie bombing in 1988 but his work lived on in Crixivan (indinavir). In combination with the antiviral agents AZT and 3TC (Lamivudine), shown with the nucleoside it imitates, indinavir revolutionized the treatment of HIV in the 1990s. Before the use of ‘combination therapy’, as it is known, most of those with HIV were dead within 2 years. Now no-one knows how long they will survive as the combination of the three drugs reduces the amount of virus to undetectably low levels. The AIDS crisis led to cooperation between the pharmaceutical companies unparalleled since the development of penicillin during the Second World War. Fifteen companies set up an AIDS drug development collaboration programme, with government agencies and universities contributing as well. The battle is not yet won, of course, and the HIV protease inhibitors have now been joined by a new generation of non-nucleoside reverse trans criptase inhibitors, such as the DuPont–Merck compound efavirenz. These commonly join the other drugs of the types mentioned above as part of the drug regimes known as ‘highly active antiretroviral therapy’ or HAART. The mixture of drugs used to combat HIV changes as discoveries are made, but life-saving combination therapy of this sort would not be possible without the sort of collaboration between organic chemists, biochemists, virologists, X-ray crystallographers, and molecular modellers that went into discovering and making indinavir. After indinavir was found to be effective, the job of the chemists was an exceptionally urgent task. They knew that a kilo of compound was needed to keep each patient alive and well for a year (newer HIV protease inhibitors require much smaller doses). Merck built a dedicated plant for the manufacture of Crixivan at Elkton, Virginia, in 1995. Within a year, production was running at full blast and there are millions of people alive today as a result.

اخر الاخبار

اخبار العتبة العباسية المقدسة

المجمع العلمي: نحو 300 ألف مستفيد من مشروع القراءة الصحيحة في كربلاء وباقي المحافظات

صحفيون: استحداث المركز الإعلامي لزيارة الأربعين أسهم في تسهيل عمل الإعلاميين وتوفير بيئة مهنية لإنجاز مهماتهم

موكب عميد بني هاشم (عليه السلام) يقدم 4500 وجبة طعام يوميًّا لزائري الأربعين

بمشاركة زائري الأربعين.. إقامة صلاة الجماعة عند مرقد أبي الفضل العباس (عليه السلام)

المزيد

الآخبار الصحية

حجم جزء محدد من الجسم يعكس الصحة العامة ومخاطر الأمراض

تفشي عدوى بكتيرية بفرنسا يحتمل ارتباطها بنوع من الجبن الطري

دراسة حديثة تكشف ما تفعله الشاشات بـ"قلوب الأطفال" !

متلازمة المبنى المريض.. هكذا يتحول تكييف الهواء إلى خطر صحي ؟؟

المزيد

الآخبار التكنلوجية

كيف تتعامل مع حرارة الطقس أثناء القيادة؟

لماذا يجب عليك إيقاف تكييف السيارة قبل إطفاء المحرك؟

دراسة تكشف سببا محتملا وراء زيادة خطر إصابة الأطفال بالتوحد

تشيلي.. العثور على متحجرة حيوان ثديي صغير من زمن الديناصورات

المزيد

مواضيع ذات صلة

The future of organic chemistry

The synthesis of oseltamivir

The synthesis of indinavir

Terpenes are volatile constituents of plants

Aromatic polyketides

Fatty acids and other polyketides are made from acetyl CoA

Benzyl isoquinoline alkaloids are made from tyrosine

Pyrrolidine alkaloids are made from the amino acid ornithine

Alkaloids are made by amino acid metabolism

The shikimic acid pathway

Phosphoenolpyruvate

Nature’s enolate equivalents: lysine enamines and coenzyme A