eTute 4 - Finding Drugs by SerendipityeTute 4 - Finding Drugs by Serendipity Flashcards
The capacity to detect an unusual drug response and recognise its potential value to other patients is fundamental to serendipitous drug discovery. But by its very nature, serendipitous drug discovery is unpredictable and haphazard, so we can’t plan for it to happen, or make it happen. Having said that - any successful development of a new drug on the basis of a serendipitous discovery usually involves three things:
1) Observant and Imaginative Researchers
A fundamental requirement is the capacity to observe an unusual drug response during human or animal testing. The relevant researchers must also appreciate the medical significance of the unexpected finding, recognising the potential for reverse translation to generate a new drug for a new medical condition. Essentially, the researchers need the imaginative capacity to link the unusual drug response to an unrelated medical condition in which patients might benefit from the novel drug effect.
2) Medicinal Chemistry Know-How
Although a serendipitous discovery uncovers a new property of a compound, the existing properties possessed by the molecule might be a problem in new patient groups. This means medicinal chemists must tinker with the chemical structure to identify “descendant molecules” that are enriched in new capabilities, but are depleted of other unnecessary effects.
As we will see below, the antibacterial Prontosil metabolite sulfanilamide was a grandfather of many medicines, but they usually had to be stripped of their antibacterial properties while also being enriched in their desirable properties. For example, one early sulfanilamide descendant used for diabetes caused unpleasant gastric side effects during extended use since its antibacterial properties killed off important microbes within the gastrointestinal tract.
3) Suitable Bioassays
After a serendipitous discovery uncovers new properties of an experimental drug, it is important that pharmacologists can develop new bioassays that allow subsequent drug analogues to be rigorously assessed for their ability to elicit the newly desired response and design new analogues. We used to use animal tissues exclusively for this, but today in vitro systems using cultured cells that express particular drug target(s) are widely employed instead.
Just as often, however, new drugs have been discovered following astute observation of unusual drug effects in animal subjects made by experimental scientists rather than clinicians.
In our hypothetical example above, the key step that led to an unexpected drug first involved doctors listening carefully as their patients reported that the drug made them feel happier. This is an example of a serendipitous discovery made by clinicians (i.e. medical practitioners) during study of drug effects in human subjects.
- Case study: Part I - Diabetes
Insulin and Diabetes
After consuming a carbohydrate-containing meal or sweet treat, sugars are released into the bloodstream from the digestive tract. Since an uncontrolled rise in sugar is harmful to many tissues, and due to the need to conserve sugar as an energy source for future needs, the pancreas releases a protein hormone known as insulin into the blood. Insulin promotes a fall in blood sugar levels by assisting glucose uptake into muscle and some other tissues.
In diabetes, a deficiency in insulin production by the pancreas ensures the body can’t properly lower blood sugar levels following the consumption of food.
In most Type 1 diabetics this is because the cells within the pancreas which normally produce insulin - the beta islet cells - are destroyed by the patient’s own overactive immune system. Type 1 diabetes is normally diagnosed in childhood, although it sometimes emerges in older patients too. For reasons that are poorly understood, Type 1 diabetes is becoming more common among Australian children (i.e., its incidence is rising).
A more common form of the disease, Type 2 diabetes , involves a partial deficiency in insulin. In these patients, the pancreas either makes too little insulin, or circulating insulin is destroyed too quickly. Another problem for many Type 2 diabetics is that the insulin produced by their pancreas fails to promote sugar uptake by muscle tissue, a situation known as insulin resistance .
Although Type 2 diabetes is most commonly diagnosed in people over the age of 35, in Australia the incidence is increasing among younger people.
Currently Type 1 diabetes accounts for about 10% of diabetic patients in Australia, while Type 2 diabetes accounts for about 85-90%.
Other forms of diabetes such as gestational diabetes which occurs in pregnant women, accounts for a few percent of total diabetes cases. This condition is potentially very serious for mothers and unborn infants.
Diabetes Treatments
Patients with Type 1 diabetes require an external source of insulin, hence a variety of insulin products are now used in clinical practice. As protein-based molecules, they can’t be administered orally because of the strongly acidic and pro-digestive conditions in the stomach, and instead must be taken via self-administered injections.
Historically, insulin extracted from the pancreas of cows (bovine insulin) or pigs (porcine insulin) was used for Type 1 diabetes, although in recent decades recombinant DNA technology has allowed the mass production of human insulin within cultured yeast cells.
Many recombinant insulin products with various durations of action within the body are now available for use by Type 1 diabetics, although they are also used by Type 2 diabetics when dietary measures and oral sugar-lowering drugs fail to control blood sugar.
As with all areas of pharmaceutical innovation, the development of the oral hypoglycaemics contains many fascinating twists and turns. A key event in the development of these diabetes drugs was a serendipitous discovery that eventually led to tolbutamide.
Several major classes of oral sugar-lowering drugs are available for use in Type 2 diabetes, known collectively as oral hypoglycaemics ( hypo = below, glyco = sugar, aemics = blood). Different oral hypoglycaemic drugs act to lower blood sugar indirectly by one of several mechanisms including altering the function of the liver or improving the responsiveness of other tissues to insulin.
