Skip Over Navigation Links

Medicines By Design

Chapter 4: Molecules to Medicines

As you've read so far, the most important goals of modern pharmacology are also the most obvious. Pharmacologists want to design, and be able to produce in sufficient quantity, drugs that will act in a specific way without too many side effects. They also want to deliver the correct amount of a drug to the proper place in the body. But turning molecules into medicines is more easily said than done. Scientists struggle to fulfill the twin challenges of drug design and drug delivery.

Medicine Hunting

While sometimes the discovery of potential medicines falls to researchers' good luck, most often pharmacologists, chemists, and other scientists looking for new drugs plod along methodically for years, taking suggestions from nature or clues from knowledge about how the body works.

Colchicine, a treatment for gout, was originally derived from the stem and seeds of the meadow saffron (autumn crocus).
Colchicine, a treatment for gout, was originally derived from the stem and seeds of the meadow saffron (autumn crocus).

Finding chemicals' cellular targets can educate scientists about how drugs work. Aspirin's molecular target, the enzyme cyclooxygenase, or COX (see No Pain, Your Gain), was discovered this way in the early 1970s in Nobel Prize-winning work by pharmacologist John Vane, then at the Royal College of Surgeons in London, England. Another example is colchicine, a relatively old drug that is still widely used to treat gout, an excruciatingly painful type of arthritis in which needle-like crystals of uric acid clog joints, leading to swelling, heat, pain, and stiffness. Lab experiments with colchicine led scientists to this drug's molecular target, a cell-scaffolding protein called tubulin. Colchicine works by attaching itself to tubulin, causing certain parts of a cell's architecture to crumble, and this action can interfere with a cell's ability to move around. Researchers suspect that in the case of gout, colchicine works by halting the migration of immune cells called granulocytes that are responsible for the inflammation characteristic of gout.

Current estimates indicate that scientists have identified roughly 500 to 600 molecular targets where medicines may have effects in the body. Medicine hunters can strategically "discover" drugs by designing molecules to "hit" these targets. That has already happened in some cases. Researchers knew just what they were looking for when they designed the successful AIDS drugs called HIV protease inhibitors. Previous knowledge of the three-dimensional structure of certain HIV proteins (the target) guided researchers to develop drugs shaped to block their action. Protease inhibitors have extended the lives of many people with AIDS.

However, sometimes even the most targeted approaches can end up in big surprises. The New York City pharmaceutical firm Pfizer had a blood pressure-lowering drug in mind, when instead its scientists discovered Viagra®, a best-selling drug approved to treat erectile dysfunction. Initially, researchers had planned to create a heart drug, using knowledge they had about molecules that make blood clot and molecular signals that instruct blood vessels to relax. What the scientists did not know was how their candidate drug would fare in clinical trials.

Sildenafil (Viagra's chemical name) did not work very well as a heart medicine, but many men who participated in the clinical testing phase of the drug noted one side effect in particular: erections. Viagra works by boosting levels of a natural molecule called cyclic GMP that plays a key role in cell signaling in many body tissues. This molecule does a good job of opening blood vessels in the penis, leading to an erection.

Back to Top

A Drug By Another Name

Drugs used to treat bone ailments may be useful for treating infectious diseases like malaria.
Drugs used to treat bone ailments may be useful for treating infectious diseases like malaria.

As pet owners know, you can teach some old dogs new tricks. In a similar vein, scientists have in some cases found new uses for "old" drugs. Remarkably, the potential new uses often have little in common with a drug's product label (its "old" use). For example, chemist Eric Oldfield of the University of Illinois at Urbana-Champaign discovered that one class of drugs called bisphosphonates, which are currently approved to treat osteoporosis and other bone disorders, may also be useful for treating malaria, Chagas' disease, leishmaniasis, and AIDS-related infections like toxoplasmosis.

Previous research by Oldfield and his coworkers had hinted that the active ingredient in the bisphosphonate medicines Fosamax®, Actonel®, and Aredia® blocks a critical step in the metabolism of parasites, the microorganisms that cause these diseases. To test whether this was true, Oldfield gave the medicines to five different types of parasites, each grown along with human cells in a plastic lab dish. The scientists found that small amounts of the osteoporosis drugs killed the parasites while sparing human cells. The researchers are now testing the drugs in animal models of the parasitic diseases and so far have obtained cures—in mice—of certain types of leishmaniasis. If these studies prove that bisphosphonate drugs work in larger animal models, the next step will be to find out if the medicines can thwart these parasitic diseases in humans.

Back to Top

21st-Century Science

While strategies such as chemical genetics can quicken the pace of drug discovery, other approaches may help expand the number of molecular targets from several hundred to several thousand. Many of these new avenues of research hinge on biology.

Relatively new brands of research that are stepping onto center stage in 21st-century science include genomics (the study of all of an organism's genetic material), proteomics (the study of all of an organism's proteins), and bioinformatics (using computers to sift through large amounts of biological data). The "omics" revolution in biomedicine stems from biology's gradual transition from a gathering, descriptive enterprise to a science that will someday be able to model and predict biology. If you think 25,000 genes is a lot (the number of genes in the human genome), realize that each gene can give rise to different variations of the same protein, each with a different molecular job. Scientists estimate that humans have hundreds of thousands of protein variants. Clearly, there's lots of work to be done, which will undoubtedly keep researchers busy for years to come.

Back to Top

A Chink in Cancer's Armor

Doctors use the drug Gleevec to treat a form of leukemia, a disease in which abnormally high numbers of immune cells
(larger, purple circles in photo) populate the blood.
Doctors use the drug Gleevec to treat a form of leukemia, a disease in which abnormally high numbers of immune cells (larger, purple circles in photo) populate the blood.

Recently, researchers made an exciting step forward in the treatment of cancer. Years of basic research investigating circuits of cellular communication led scientists to tailor-make a new kind of cancer medicine. In May 2001, the drug Gleevec™ was approved to treat a rare cancer of the blood called chronic myelogenous leukemia (CML). The Food and Drug Administration described Gleevec's approval as "...a testament to the groundbreaking scientific research taking place in labs throughout America."

Researchers designed this drug to halt a cell-communication pathway that is always "on" in CML. Their success was founded on years of experiments in the basic biology of how cancer cells grow. The discovery of Gleevec is an example of the success of so-called molecular targeting: understanding how diseases arise at the level of cells, then figuring out ways to treat them. Scores of drugs, some to treat cancer but also many other health conditions, are in the research pipeline as a result of scientists' eavesdropping on how cells communicate.

Back to Top

Rush Delivery

Finding new medicines and cost-effective ways to manufacture them is only half the battle. An enormous challenge for pharmacologists is figuring out how to get drugs to the right place, a task known as drug delivery.

Ideally, a drug should enter the body, go directly to the diseased site while bypassing healthy tissue, do its job, and then disappear. Unfortunately, this rarely happens with the typical methods of delivering drugs: swallowing and injection. When swallowed, many medicines made of protein are never absorbed into the bloodstream because they are quickly chewed up by enzymes as they pass through the digestive system. If the drug does get to the blood from the intestines, it falls prey to liver enzymes. For doctors prescribing such drugs, this first-pass effect (see A Drug's Life) means that several doses of an oral drug are needed before enough makes it to the blood. Drug injections also cause problems, because they are expensive, difficult for patients to self-administer, and are unwieldy if the drug must be taken daily. Both methods of administration also result in fluctuating levels of the drug in the blood, which is inefficient and can be dangerous.

What to do? Pharmacologists can work around the first-pass effect by delivering medicines via the skin, nose, and lungs. Each of these methods bypasses the intestinal tract and can increase the amount of drug getting to the desired site of action in the body. Slow, steady drug delivery directly to the bloodstream—without stopping at the liver first—is the primary benefit of skin patches, which makes this form of drug delivery particularly useful when a chemical must be administered over a long period.

Hormones such as testosterone, progesterone, and estrogen are available as skin patches. These forms of medicines enter the blood via a meshwork of small arteries, veins, and capillaries in the skin. Researchers also have developed skin patches for a wide variety of other drugs. Some of these include Duragesic® (a prescription-only pain medicine), Transderm Scop® (a motion-sickness drug), and Transderm Nitro® (a blood vessel-widening drug used to treat chest pain associated with heart disease). Despite their advantages, however, skin patches have a significant drawback. Only very small drug molecules can get into the body through the skin.

Inhaling drugs through the nose or mouth is another way to rapidly deliver drugs and bypass the liver. Inhalers have been a mainstay of asthma therapy for years, and doctors prescribe nasal steroid drugs for allergy and sinus problems. Researchers are investigating insulin powders that can be inhaled by people with diabetes who rely on insulin to control their blood sugar daily. This still-experimental technology stems from novel uses of chemistry and engineering to manufacture insulin particles of just the right size. Too large, and the insulin particles could lodge in the lungs; too small, and the particles will be exhaled. If clinical trials with inhaled insulin prove that it is safe and effective, then this therapy could make life much easier for people with diabetes.

Back to Top

Reading a Cell MAP

Kinases are enzymes that add phosphate groups (red-yellow structures) to proteins (green), assigning the proteins a code. In this reaction, an intermediate molecule called ATP (adenosine triphosphate) donates a phosphate group from itself, becoming ADP (adenosine diphosphate).
Kinases are enzymes that add phosphate groups (red-yellow structures) to proteins (green), assigning the proteins a code. In this reaction, an intermediate molecule called ATP (adenosine triphosphate) donates a phosphate group from itself, becoming ADP (adenosine diphosphate).

Scientists try hard to listen to the noisy, garbled "discussions" that take place inside and between cells. Less than a decade ago, scientists identified one very important cellular communication stream called MAP (mitogen-activated protein) kinase signaling. Today, molecular pharmacologists such as Melanie H. Cobb of the University of Texas Southwestern Medical Center at Dallas are studying how MAP kinase signaling pathways malfunction in unhealthy cells.

Some of the interactions between proteins in these pathways involve adding and taking away tiny molecular labels called phosphate groups. Kinases are the enzymes that add phosphate groups to proteins, and this process is called phosphorylation. Marking proteins in this way assigns the proteins a code, instructing the cell to do something, such as divide or grow. The body employs many, many signaling pathways involving hundreds of different kinase enzymes. Some of the important functions performed by MAP kinase pathways include instructing immature cells how to "grow up" to be specialized cell types like muscle cells, helping cells in the pancreas respond to the hormone insulin, and even telling cells how to die.

Since MAP kinase pathways are key to so many important cell processes, researchers consider them good targets for drugs. Clinical trials are under way to test various molecules that, in animal studies, can effectively lock up MAP kinase signaling when it's not wanted, for example, in cancer and in diseases involving an overactive immune system, such as arthritis. Researchers predict that if drugs to block MAP kinase signaling prove effective in people, they will likely be used in combination with other medicines that treat a variety of health conditions, since many diseases are probably caused by simultaneous errors in multiple signaling pathways.

Back to Top

Transportation Dilemmas

Scientists are solving the dilemma of drug delivery with a variety of other clever techniques.Many of the techniques are geared toward sneaking through the cellular gate-keeping systems' membranes. The challenge is a chemistry problem—most drugs are water-soluble, but membranes are oily. Water and oil don't mix, and thus many drugs can't enter the cell. To make matters worse, size matters too. Membranes are usually constructed to permit the entry of only small nutrients and hormones, often through private cellular alleyways called transporters.

Proteins that snake through membranes help
transport molecules into cells.
Proteins that snake through membranes help transport molecules into cells.

Many pharmacologists are working hard to devise ways to work not against, but with nature, by learning how to hijack molecular transporters to shuttle drugs into cells. Gordon Amidon, a pharmaceutical chemist at the University of Michigan-Ann Arbor, has been studying one particular transporter in mucosal membranes lining the digestive tract. The transporter, called hPEPT1, normally serves the body by ferrying small, electrically charged particles and small protein pieces called peptides into and out of the intestines.

Amidon and other researchers discovered that certain medicines, such as the antibiotic penicillin and certain types of drugs used to treat high blood pressure and heart failure, also travel into the intestines via hPEPT1. Recent experiments revealed that the herpes drug Valtrex® and the AIDS drug Retrovir® also hitch a ride into intestinal cells using the hPEPT1 transporter. Amidon wants to extend this list by synthesizing hundreds of different molecules and testing them for their ability to use hPEPT1 and other similar transporters. Recent advances in molecular biology, genomics, and bioinformatics have sped the search for molecules that Amidon and other researchers can test.

Scientists are also trying to slip molecules through membranes by cloaking them in disguise. Steven Regen of Lehigh University in Bethlehem, Pennsylvania, has manufactured miniature chemical umbrellas that close around and shield a molecule when it encounters a fatty membrane and then spread open in the watery environment inside a cell. So far, Regen has only used test molecules, not actual drugs, but he has succeeded in getting molecules that resemble small segments of DNA across membranes. The ability to do this in humans could be a crucial step in successfully delivering therapeutic molecules to cells via gene therapy.

Back to Top

Act Like a Membrane

Researchers know that high concentrations of chemotherapy drugs will kill every single cancer cell growing in a lab dish, but getting enough of these powerful drugs to a tumor in the body without killing too many healthy cells along the way has been exceedingly difficult. These powerful drugs can do more harm than good by severely sickening a patient during treatment.

David Needham designed liposomes resembling tiny molecular 'soccer balls' made from two different oils that wrap around a drug.
David Needham designed liposomes resembling tiny molecular "soccer balls" made from two different oils that wrap around a drug.

Some researchers are using membrane-like particles called liposomes to package and deliver drugs to tumors. Liposomes are oily, microscopic capsules that can be filled with biological cargo, such as a drug. They are very, very small—only one one-thousandth the width of a single human hair. Researchers have known about liposomes for many years, but getting them to the right place in the body hasn't been easy. Once in the bloodstream, these foreign particles are immediately shipped to the liver and spleen, where they are destroyed.

Materials engineer David Needham of Duke University in Durham, North Carolina, is investigating the physics and chemistry of liposomes to better understand how the liposomes and their cancer-fighting cargo can travel through the body. Needham worked for 10 years to create a special kind of liposome that melts at just a few degrees above body temperature. The end result is a tiny molecular "soccer ball" made from two different oils that wrap around a drug. At room temperature, the liposomes are solid and they stay solid at body temperature, so they can be injected into the bloodstream. The liposomes are designed to spill their drug cargo into a tumor when heat is applied to the cancerous tissue. Heat is known to perturb tumors, making the blood vessels surrounding cancer cells extra-leaky. As the liposomes approach the warmed tumor tissue, the "stitches" of the miniature soccer balls begin to dissolve, rapidly leaking the liposome's contents.

Needham and Duke oncologist Mark Dewhirst teamed up to do animal studies with the heat-activated liposomes. Experiments in mice and dogs revealed that, when heated, the drug-laden capsules flooded tumors with a chemotherapy drug and killed the cancer cells inside. Researchers hope to soon begin the first stage of human studies testing the heat-triggered liposome treatment in patients with prostate and breast cancer. The results of these and later clinical trials will determine whether liposome therapy can be a useful weapon for treating breast and prostate cancer and other hard-to-treat solid tumors.

Back to Top

Anesthesia Dissected

Scientists who study anesthetic medicines have a daunting task—for the most part, they are "shooting in the dark" when it comes to identifying the molecular targets of these drugs. Researchers do know that anesthetics share one common ingredient: Nearly all of them somehow target membranes, the oily wrappings surrounding cells. However, despite the fact that anesthesia is a routine part of surgery, exactly how anesthetic medicines work in the body has remained a mystery for more than 150 years. It's an important problem, since anesthetics have multiple effects on key body functions, including critical processes such as breathing.

Scientists define anesthesia as a state in which no movement occurs in response to what should be painful. The problem is, even though a patient loses a pain response, the anesthesiologist can't tell what is happening inside the person's organs and cells. Further complicating the issue, scientists know that many different types of drugs—with little physical resemblance to each other—can all produce anesthesia. This makes it difficult to track down causes and effects.

Anesthesiologist Robert Veselis of the Memorial Sloan-Kettering Institute for Cancer Research in New York City clarified how certain types of these mysterious medicines work. Veselis and his coworkers measured electrical activity in the brains of healthy volunteers receiving anesthetics while they listened to different sounds. To determine how sedated the people were, the researchers measured reaction time to the sounds the people heard. To measure memory effects, they quizzed the volunteers at the end of the study about word lists they had heard before and during anesthesia. Veselis' experiments show that the anesthetics they studied affect separate brain areas to produce the two different effects of sedation and memory loss. The findings may help doctors give anesthetic medicines more effectively and safely and prevent reactions with other drugs a patient may be taking.

Back to Top

The G Switch

Imagine yourself sitting on a cell, looking outward to the bloodstream rushing by. Suddenly, a huge glob of something hurls toward you, slowing down just as it settles into a perfect dock on the surface of your cell perch. You don't realize it, but your own body sent this substance—a hormone called epinephrine—to protect you, telling you to get out of the way of a car that just about sideswiped yours while drifting out of its lane. Your body reacts, whipping up the familiar, spine-tingling, "fight-or-flight" response that gears you to respond quickly to potentially threatening situations such as this one.

A hormone (red) encounters a receptor
(blue) in the membrane of a cell.
G proteins act like relay batons to pass messages from circulating hormones into cells. A hormone (red) encounters a receptor (blue) in the membrane of a cell.
A G protein (green) becomes activated
and makes contact with the receptor to which the hormone is attached.
A G protein (green) becomes activated and makes contact with the receptor to which the hormone is attached.
The G protein passes the hormone's
message to the cell by switching on a cell enzyme (purple) that triggers a response.
The G protein passes the hormone's message to the cell by switching on a cell enzyme (purple) that triggers a response.

How does it all happen so fast?

Getting into a cell is a challenge, a strictly guarded process kept in control by a protective gate called the plasma membrane. Figuring out how molecular triggers like epinephrine communicate important messages to the inner parts of cells earned two scientists the Nobel Prize in physiology or medicine in 1994. Getting a cellular message across the membrane is called signal transduction, and it occurs in three steps. First, a message (such as epinephrine) encounters the outside of a cell and makes contact with a molecule on the surface called a receptor. Next, a connecting transducer, or switch molecule, passes the message inward, sort of like a relay baton. Finally, in the third step, the signal gets amplified, prompting the cell to do something: move, produce new proteins, even send out more signals.

One of the Nobel Prize winners, pharmacologist Alfred G. Gilman of the University of Texas Southwestern Medical Center at Dallas, uncovered the identity of the switch molecule, called a G protein. Gilman named the switch, which is actually a huge family of switch molecules, not after himself but after the type of cellular fuel it uses: an energy currency called GTP. As with any switch, G proteins must be turned on only when needed, then shut off. Some illnesses, including fatal diseases like cholera, occur when a G protein is errantly left on. In the case of cholera, the poisonous weaponry of the cholera bacterium "freezes" in place one particular type of G protein that controls water balance. The effect is constant fluid leakage, causing life-threatening diarrhea.

In the few decades since Gilman and the other Nobel Prize winner, the late National Institutes of Health scientist Martin Rodbell, made their fundamental discovery about G protein switches, pharmacologists all over the world have focused on these signaling molecules. Research on G proteins and on all aspects of cell signaling has prospered, and as a result scientists now have an avalanche of data. In the fall of 2000, Gilman embarked on a groundbreaking effort to begin to untangle and reconstruct some of this information to guide the way toward creating a "virtual cell." Gilman leads the Alliance for Cellular Signaling, a large, interactive research network. The group has a big dream: to understand everything there is to know about signaling inside cells. According to Gilman, Alliance researchers focus lots of attention on G proteins and also on other signaling systems in selected cell types. Ultimately, the scientists hope to test drugs and learn about disease through computer modeling experiments with the virtual cell system.

Back to Top

Got It?

What is a liposome?

Name three drug delivery methods.

Describe how G proteins work.

What do kinases do?

Discuss the "omics" revolution in biomedical research.

This page last reviewed on October 27, 2011