eTute 2 - Bioprospecting: New Drugs from NatureeTute 2 - Bioprospecting: New Drugs from Nature Flashcards
These bioactive molecules are typically secondary metabolites - that is, they’re produced by plants to carry out some kind of supporting role within the plant’s tissues (this differs from primary metabolites that are absolutely essential for plant growth).
Since they go to so much trouble to make them, there must be something in it for the plants. But what exactly?
- Pest deterrents: Plants are stationary organisms that can’t run away when confronted by predators. One of their defensive strategies involves engaging in a form of chemical warfare by making molecules that make their leaves toxic or bad-tasting to insects. Some of these molecules might have interesting biological properties that make them useful as human medicines.
- Growth regulations: Some secondary metabolites produced by plants may help to regulate the growth of stems, leaves or roots. This can include roles in regulating the expression of genes needed during the assembly of new plant cells or tissue structures. This allows plants to respond quickly to environmental stresses or alterations in climactic conditions like, for example, the change of seasons.
The path a molecule takes as it travels from the lab bench to end up as a pill in a bottle on a pharmacy shelf is very unpredictable, but a number of key stages are usually involved.
- Cellular communication: Due to their structural complexity, growing plants need to coordinate the behaviour of cells in different parts of the plant. They do this using a chemical language in which small molecules are released to allow signalling between different cells, prompting their neighbours to actively grow, remain static, or undergo cell death.
Nowadays, drug discovery projects often source their plant samples within densely vegetated regions such as tropical jungles that exhibit high botanical diversity. In its early stages, the drug discovery team often includes cultural anthropologists who study the medical practices of indigenous tribes to determine whether any plants from the local environment are believed to be useful for particular ailments. In any drug discovery program involving naturally-sourced plant matter, it is important that the human and environmental impact of plant collection and harvesting is taken into account.
- Natural sunblock: Plants need sunscreen to withstand the daily cycle of exposure to damaging UV irradiation produced by the sun. Unable to retreat to the shade, the leaves of many plants produce substances that act as natural versions of titanium oxide, the sunblock constituent that absorbs high energy UV radiation, thereby protecting cellular components such as DNA and proteins.
1) Plant Selection
A particular species of plant may attract scientific interest for many reasons, but in some famous cases, it originated in the medical folklore of a particular tribe or society.
In its early stages, the drug discovery team often includes cultural anthropologists who study the medical practices of indigenous tribes to determine whether any plants from the local environment are believed to be useful for particular ailments.
Crushing the plant samples liberates the bioactive molecules of concern which are then extracted using solvents such as water or alcohol.
2) Extract Preparation
The secondary metabolites of interest are typically embedded within plant cell structures that are often tough and woody. Crushing the plant samples liberates the bioactive molecules of concern which are then extracted using solvents such as water or alcohol. In most cases, the resulting crude extract is very complex in chemical terms, containing hundreds or thousands of molecules. It’s like an exciting soup of potential.
In any drug discovery program involving naturally-sourced plant matter, it is important that the human and environmental impact of plant collection and harvesting is taken into account.
In most cases, the resulting crude extract is very complex in chemical terms, containing hundreds or thousands of molecules. It’s like an exciting soup of potential.
Fewer molecules means there is less likelihood of complex interactions between different extract constituents, so fractions are usually more useful in bioassays than the original crude extracts.
3) Extract Fractionation
Due to the complexity of the crude extract (the exciting soup), chemists often prepare fractions that are essentially simplified extracts containing smaller numbers of molecules.
5) Compound Identification
Once a particular plant-derived fraction is found to contain bioactives of interest, chemists try to identify and isolate the chemical compounds that are responsible for the pharmacological activity.
4) Bioassay Screening
To determine whether they contain bioactive molecules, scientists conduct large-scale screening in which the various fractions are evaluated for their effects
In a simple example, researchers looking for new anti-cancer drugs might simply test a series of fractionated plant extracts for their ability to kill cultured tumour cells.
upon simple biological systems. This can be done using cultured cells grown on multi-well plates that enable many different samples to be evaluated simultaneously.
Hundreds if not thousands of different bioassays are used in modern drug discovery research, all with a view to identifying plant-derived fractions that contain molecules with interesting pharmacological properties.
They need expertise in natural product chemistry, and this has been crucial to modern pharmacology. In modern instrumental analysis, mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy are the main experimental tools used by chemists to identify new plant-derived bioactives.
These include experiments conducted using cultured cells, but usually proceed to various species of lab animals including rats and mice.
6) Animal Testing
Once a pure bioactive compound is available, it is subjected to a larger range of tests that provide a fuller knowledge of its pharmacological characteristics.
Animal testing of drugs in modern drug discovery is subject to extensive ethical and regulatory oversight. Essentially, drug testing in animals is intended to meet two basic needs.
First, it seeks to establish whether a new molecule is effective for the disease of concern and second, whether it is safe for human use. Note that animal testing is only reserved for molecules that have already shown promise in cell-based in vitro test systems.
7) Human Testing
If sufficient proof is obtained that a plant-derived bioactive is safe and effective in animals, human testing can begin.
Conducting human trials of new drugs is a complicated and demanding process, so only the most promising molecules ever enter this costly stage.
Human testing involves multiple phases so that ineffective or unsafe molecules can be identified and their development discontinued.
8) Regulatory Approval
Once a drug is proven to be safe and effective in humans, a marketing approval application can be submitted to a government agency that regulates the licensing of medicines in particular jurisdictions.
Due to the huge amount of data needed to support drug approval applications, this complex process involves months of evaluation of enormous data-dense drug company dossiers by government assessors and academic expert reviewers.
9) Marketing
Once a drug application is approved by the relevant government agency, it can be made available for use by doctors and patients. Advertising campaigns then inform doctors about the availability of the new medicine.
If all goes to plan, the new medicine helps to enhance human well-being by providing patients with remedies for their medical problems.
Yet the availability of a new drug also raises the prospect of unexpected harm, hence post-marketing surveillance networks are established to monitor the frequency of any harmful effects that new drugs might cause when used by large numbers of patients.
- Morphine (1804)
The opium poppy has long been known for its euphoric properties. The active ingredient morphine was first isolated from dried poppy resin by a 20 year old German pharmacy apprentice named Friedrich W.
Sertürner (1783-1841). He then confirmed its sleep-inducing effects in dogs, prompting him to name the drug after Morpheus, the Greek god of dreams. Sertürner’s experimental methods were quickly adopted by other European researchers, leading to the isolation of many plant-derived drugs in the first half of the nineteenth century.
Used widely to treat moderate to severe pain, morphine remains the gold standard against which other painkillers are tested.
Its mild CNS (central nervous system) stimulatory properties ensure caffeine is a widely consumed constituent of soft drinks, coffee, tea and cocoa beverages as well as over-the-counter remedies for drowsiness and the common cold.
