Bio Screening Industry News

This publication, showing data from the testing of Quinazoline derivatives in a Spinal Muscular Atrophy mouse model, has been published in Human Molecular Genetics by lead author Dr. Matthew Butchbach from the laboratory of Dr. Arthur Burghes at the Ohio State University.

The generation of the Quinazoline compounds as a therapeutic drug candidate for Spinal Muscular Atrophy was fully funded by Families of SMA.

The paper explores whether the Quinazoline compounds, which increase the expression of SMN2, are useful as potential therapeutics for SMA. Ultrahigh-throughput screening identified substituted Quinazolines as potent SMN2 inducers.  The drug-like properties of the initial screening hits were optimized through directed medicinal chemistry.  This resulted in series of C5-Quinazoline derivatives.

Oral administration of three of these compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system.  The authors then examined the effect of these compounds on the progression of disease in SMNDelta7 SMA mice.  Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss.  Overall the authors summarize that the quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11, and ameliorates the motor phenotype of SMNDelta7 SMA mice.

“This is the first compound series to go from hit-to-preclinical candidate that shows favorable pharmacology in the nervous system and shows benefit to severe SMA mice.  This study shows that promising therapies for SMA can be developed”, said Matthew Butchbach, Ph.D., who is lead author on this publication.

“Families of SMA is pleased that the first test of this class of compounds in SMA mice shows potential therapeutic benefit.  The clinical lead in this series called Quinazoline495, which is a more optimized compound than those tested here, has also been assessed in this animal model with similar results, as well as tested in a slightly less severe mouse model of SMA, in which it showed marked enhancement of survival”, says Jill Jarecki, Ph.D., FSMA research director.

The lead compound Quinazoline495 recently received orphan drug designation from the FDA for the treatment of spinal muscular atrophy.  Please click here to read more.

Families of SMA recently licensed this series of compounds to Repligen Corporation for development as a drug treatment for Spinal Muscular Atrophy.

The full reference:

European chemists have discovered that both mirror-image forms of a particular compound can bind at the same time in the same site of an enzyme, a phenomenon that has never been seen before. The finding has significance for drug discovery screening and studies of how small molecules interact with proteins.

Rolf Breinbauer from Graz University of Technology, Austria, and Wulf Blankenfeldt from the Max Planck Institute of Molecular Physiology in Dortmund, Germany, were studying a metabolic enzyme from a species of the bacterium Burkholderia cepacia, using racemic mixtures of chiral probe molecules to find ones that bound in the enzyme’s active site. In most cases only one form of a chiral (or ‘handed’) molecule would bind at once, but they found that in one instance both enantiomeric forms occupied the binding site at the same time.

‘If you read the textbooks about enantiomers,’ says Breinbauer, ‘there’s a simplified notion that one enantiomer is good and the other is either bad or just idle.’ He explains that for most proteins (apart from certain enzymes that have evolved to cope with wide ranges of substrate molecules) either only one enantiomer will bind, or both can bind individually - with the assumption that one form will be significantly more active than the other. ‘Our findings show that the world is more complicated,’ he adds.

While each individual enantiomer can bind to the enzyme seperately, Breinbauer notes that the arrangement of the molecules within the binding site is quite different when both bind together. This could lead to cooperative effects, producing either an enhanced or diminished response relative to the individual enantiomers.

He adds that this could have relevance in drug discovery screening, where mixtures of both enantiomers of chiral compounds are routinely screened together to find initial hits. ‘People need to consider more options when interpreting binding data from racemic mixtures.’

Dafydd Owen of Pfizer Research Chemistry in  Sandwich, UK, agrees that the finding is an important reminder that chemists need to be open-minded about interpreting screening data. It also highlights the inherent trade-offs made when screening mixtures - particularly in high-throughput screens when mixtures of several compounds are tested at once.

Owen sees most interest in the discovery in the area of fragment-based drug discovery, where small ‘fragment’ molecules found to bind to a drug target are linked together to make potential drug molecules. ‘As a medicinal chemist,’ he adds, ‘my immediate thought was to join the two structures together to incorporate the best of each and make a hybrid.’ He points out, however, that from a fragment point of view it is almost irrelevant to the enzyme that the two molecules happen to be mirror images of each other, ‘despite their apparent similarity, nature views enantiomers as very different molecules’.

Phillip Broadwith

Source: rsc.org

Using a pair of tweezers, a UT graduate student carefully lifted a nylon mesh square about the size of a thumbnail out of a small flask in his team’s lab.

The nylon had been soaking in a clear, watery solution containing a chemical compound — the “capture agent” — that it would bind with during a process tweaked by the student and his team.

Jennifer Brodbelt, a chemistry and biochemistry professor, received a $734,068 grant from the National Institutes of Health Oct. 1 to further develop the process — Desorption Electrospray Ionization (TM-DESI) — and perfect the nylon squares which isolate desired compounds from solutions.

Brodbelt, UT graduate students and two professors from Southwestern University in Georgetown were given a two-year deadline to gather blood from people of varying ages and levels of health, and to develop a more efficient method of analyzing the samples.

Results will be used to spot trends in the frequency of certain biological compounds, including amino acids.

A mass spectrometer, the machine Brodbelt’s team uses, can identify specific compounds in a mixture like blood. The tricky part was getting the sample to spray into the machine.

Joe Chipuk, a graduate student currently working on the project, was struck by the idea of having samples sprayed directly through a sifting material into the spectrometer.

Chipuk ran home and began collecting mesh materials to spray water through. He cut up his screen door, his wife’s tea strainer and the aerator from his kitchen faucet.

He went outside, used a hose to spray water through the mesh materials and observed the water’s exit path.

He then drafted a plan to create a mesh material soaked in a chemical that allows certain compounds to travel through but traps enough as to not let every metabolite escape.

After the unwanted materials are sorted out, the desired compounds attached to the mesh are released and analyzed by the spectrometer.

Before Chipuk’s square, the desorption process played out very much like a complicated billiards shot. The spray came down at an angle, hit the slide holding the blood sample and ricocheted off carrying the compounds through the spectrometer.

The new technique allows the compounds to be sorted and analyzed at a much faster pace than before. Chipuk said they can now analyze 50 samples in approximately eight minutes, whereas before, analyzing 50 samples would have taken more than 24 hours.

The team is focusing on improving the reliability and consistency of the mesh squares, Brodbelt said.

“The hope is that this could be a way to diagnose patterns of disease or determine a prognosis based on the pattern of metabolites,” Brodbelt said. “The sooner you have an idea that you might have cancer, or that you are on track to develop cancer, you could have screening done earlier and more frequently.”

Source: dailytexanonline.com

Scientists at the University of North Carolina at Chapel Hill School of Medicine and the University of California, San Francisco have developed and experimentally tested a technique to predict new target diseases for existing drugs.

The researchers developed a computational method that compares how similar the structures of all known drugs are to the naturally occurring binding partners — known as ligands — of disease targets within the cell. In a study published this week in Nature, the scientists showed that the method predicts potential new uses as well as unexpected side effects of approved drugs.”This approach uncovered interactions between drugs and targets that we never could have predicted simply by looking at the chemical structures,” said senior study author Bryan Roth, M.D., Ph.D., professor of pharmacology and director of the National Institute of Mental Health Psychoactive Drug Screening Program at UNC. “We may now have a way to predict what side effects are likely to occur from treatment before we even put a drug into clinical testing.” Roth is also a member of the UNC Lineberger Comprehensive Cancer Center.

Many of the most successful drugs on the market today are being prescribed for ailments that are quite different from the ones they were originally designed to treat. Viagra, for instance, was once intended for coronary heart disease but now is used to combat erectile dysfunction. The discovery of surprising uses of developed drugs can sometimes be the result of serendipity, as unforeseen side effects emerge from clinical trials. In the past, researchers have tried to predict drug interactions by looking for chemical similarities among the possible targets of pharmaceutical compounds.

However, some drug targets which look very similar to one another bind very different ligands, and some targets that don’t have any obvious similarity bind similar ligands, says Brian Shoichet, Ph.D., co-senior study author and professor of pharmaceutical chemistry at the University of California at San Francisco. “So if instead we were to organize targets by the ligands they recognize, it could reveal different patterns than traditional approaches, and illuminate new opportunities for drugs to bind to unexpected targets.”

A team of researchers led by Roth and Shoichet did just that, comparing the structures of 3,365 FDA-approved and investigational drugs against the structures of hundreds of targets, defining each target by its ligands. They then honed in on thirty of the strongest predictions, validating the actual physical interactions between the drugs and targets in wet laboratory experiments.

In one of their follow-up experiments, the scientists investigated the molecular targets of the hallucinogenic substance dimethyltrytamine (DMT), which had previously been postulated to act through a site known as the sigma-1 receptor. Using the computational approach, Roth and colleagues found that DMT had a high affinity for serotonin receptors, including the binding site for LSD, another hallucinogen.

They also showed that the substance is hallucinogenic in normal mouse models but not in ones lacking the serotonin receptor. Roth says the power of their approach is it can be used to uncover the real targets of pharmaceutical compounds quickly and efficiently, and will probably lead to a greater understanding of the many molecular targets of each drug.

“Drugs are not as selective as we once thought,” said Roth, who is also a professor in the School of Pharmacy’s medicinal chemistry and natural products division. “It turns out that the most non-selective drugs are frequently the most effective for complex diseases. Rather than ‘magic bullets,’ we need to come up with ‘magic shotguns’ that hit more than one molecular target at a time. We could use this computational approach to identify the drugs that hit the right targets and miss the wrong ones.”

Study co-authors from UNC include Vincent Setola, research associate professor; Atheir Abbas, former graduate student; Sandra J. Hufeisen, senior research assistant; Niels H. Jensen, research associate; Michael B. Kuijer, research technician; Roberto C. Matos, research technician; Thuy B. Tran, research technician; Ryan Whaley, research technician; and Richard A. Glennon. The paper’s first author is Dr. Michael Keiser, from the UCSF side of the collaboration. Also from UCSF were Drs. John Irwin, Christian Laggner and Jerome Hert, and PharmDs Kelan Thomas and Douglas Edwards.

Funding for the studies at UNC and at UCSF came from the National Institutes of Health.

ScienceDaily (Nov. 7, 2009)

AUSTIN, Texas — Dr. Jennifer Brodbelt, professor of chemistry and biochemistry at The University of Texas at Austin, has received a $734,068 grant from the National Institutes of Health (NIH) to develop a new method for rapidly screening blood samples for biomarkers.

Biomarkers are small molecules that indicate the presence of a particular physiological condition, typically a disease. The new method, if successful, could prove useful not just for identifying markers of specific diseases such as cancer or heart disease, but for discovering broader metabolic patterns correlated with conditions such as aging or obesity.

“There are technologies right now that are very effective at separating and analyzing the different compounds in a blood sample, but they tend to be relatively slow,” says Brodbelt, the principal investigator of the grant. “It makes it very hard to do analyses of lots of samples. What we’re developing is a chip-based method, where entire classes of compounds are captured on the chips and then all the compounds are released and analyzed by mass spectrometry in just a few seconds.”

Although the technology, if successful, should be useful in searching for biomarkers in all sorts of conditions, Brodbelt and her collaborators from Southwestern University in Georgetown, Texas, Drs. Lynn and Frank Guziec, are focusing on patterns that correlate with aging.

“We’re trying to develop maps that can correlate the progression of aging with metabolites that might be circulating in your blood,” says Brodbelt. “These could be small molecules that increase in quantity as you age, or actually change in composition as one ages.”

The new method, says Brodbelt, involves three basic stages.

The first stage is the coating of different regions of a mesh chip with a variety of “capture agents,” which chemically bind to specific compounds in a blood sample. A burst from an ultraviolet light then severs the chemical bonds between the chip and the captured substances. Then an electrospray, which is similar to a solvent aerosol spray, shoots through the mesh chip and transfers the different compounds into the mass spectrometer for analysis.

By analyzing the mass spectrometric data, says Brodbelt, scientists should be able to measure the presence and quantity of different compounds, and to do so on a scale, and with a speed, that wasn’t possible before.

“The payoff could be big,” she says. “It’s a different strategy than what might be pursued by molecular biologists or biochemists. They’ll often focus on studying one or two proteins at a time, and develop a really deep understanding of those proteins. We’re looking for the more generalized profile, and we may notice some patterns that weren’t apparent to them.

“There are so many other areas where you’d want to do profiling. It might involve looking for pesticides as part of an environmental study, or doing protein-related work or drug profiling work. If this approach is successful, I imagine other groups will try to develop these chips as well.”

Brodbelt’s grant, which is being funded as part of the American Recovery and Reinvestment Act (ARRA) government stimulus package, is a “Challenge Grant,” meant to encourage high-risk, high-reward research projects that may produce results quickly.

This is the second NIH grant in two years that Brodbelt and the Guziecs have received. In 2008, the collaborating groups received a four-year, $1,113,615 grant to evaluate an innovative technique that could assess the anti-cancer activity of new compounds.

For more information, contact: Jennifer Brodbelt, Department of Chemistry and Biochemistry, 512-471-0028.

Using a recently described monolayer assay amenable to high throughput screening format for the identification of potential Nipah virus and Hendra virus antivirals, we have partially screened a low molecular weight compound library (>8,000 compounds) directly against live virus infection and identified twenty eight promising lead molecules. Initial single blind screens were conducted with 10 microM compound in triplicate with a minimum efficacy of 90% required for lead selection.

Lead compounds were then further characterised to determine the median efficacy (IC50), cytotoxicity (CC50) and the in vitro therapeutic index in live virus and pseudotype assay formats.

Results: While a number of leads were identified, the current work describes three commercially available compounds: brilliant green, gentian violet and gliotoxin, identified as having potent antiviral activity against Nipah and Hendra virus. Similar efficacy was observed against pseudotyped Nipah and Hendra virus, vesicular stomatitis virus and human parainfluenza virus type 3 while only gliotoxin inhibited an influenza A virus suggesting a non-specific, broad spectrum activity for this compound.

Conclusions: All three of these compounds have been used previously for various aspects of anti-bacterial and anti-fungal therapy and the current results suggest that while unsuitable for internal administration, they may be amenable to topical antiviral applications, or as disinfectants and provide excellent positive controls for future studies.

Author: Mohamad AljofanMichael SgangaMichael LoChristine RootesMatteo PorottoAdam MeyerSimon SaubernAnne MosconaBruce Mungall
Credits/Source: Virology Journal 2009, 6:187

The findings about this compound, published in the Nov. 3 issue of Biochemistry journal, might prove valuable to patients and clinicians, who may benefit if there is a demonstrated boost to chemotherapy. Researchers also can use the compound to manipulate the receptor to learn more about a common cell replenishing pathway, called the Wnt pathway, which requires the receptor for normal activities and can go wrong in cancer cases.

The researchers had a choice: to screen libraries of several hundred thousand biochemical compounds or to use a library of about 1,200 FDA approved or biologically active compounds.

“We decided to take the less expensive route of screening FDA approved drugs, and fortunately, we found 26 compounds that seemed to meet our goal, but only one that truly worked with the Frizzled receptor,”said Wei Chen, Ph.D., Assistant Professor of the Department of Medicine at Duke. “The goal was to drive the Frizzled 1 receptor from the outer membrane to the inside of the cell,” which effectively inactivated the receptor.

The effective compound, niclosamide, is currently approved for use against tapeworm infection. But some colon cancer patients, for example, have a Wnt pathway that is overactivated and may benefit from the “quieting” effects of niclosamide, which blocks the receptor in the Wnt pathway.

“The paper provides a rationale for clinicians to investigate using niclosamide for a new purpose,” Dr. Chen said. “Based on our findings, one oncologist at Duke is writing protocols for a phase 1 (safety) clinical trial to treat colon cancer patients with the intention of bringing our laboratory findings to the patient’s bedside.”

Chen says he is proud of the work, which is “truly translational science.”

“I am a basic scientist working with cell receptors, we have a medicinal chemist in our laboratory and one of our collaborators is Dr. H. Kim Lyerly, a professor of surgery, who is a researcher in gene- and immune-based therapies for cancer, as well as director of the Duke Comprehensive Cancer Center,” said Chen. “This type of diverse collaboration lets me shepherd a finding more rapidly from the laboratory to the clinic.”

Provided by Duke University Medical Center

physorg.com

Slow procedure

It takes 15 years on average for a drug discovery to make it to a patient’s medicine cabinet. Throughout the process, the U.S. Food and Drug Administration requires drug companies to submit applications to proceed to the next step.

1 Drug discovery and preclinical research (three to six years) – Researchers search for candidate drugs by screening chemical compounds that contain thousands or millions of potential medicines. They test the candidates against the disease target.

Once a compound has shown some activity against the drug target, it undergoes extensive testing in the lab – both in test tubes and animals. Years of preclinical testing must establish that the candidate medicine is likely to be safe and effective in humans before clinical testing can begin.

2 Clinical trials (six to seven years) – When a company is ready to begin clinical trials, it submits an Investigational New Drug Application to the FDA showing the data it has gathered in preclinical tests, as well as a clinical studies plan or protocol. Testing occurs in three phases:

Phase 1 – A small group of healthy people is tested to see how the chemical compound affects the body.

Phase 2 – The drug is tested in patients who have the disease in question.

Phase 3 – The drug is tested in hundreds or thousands of patients to find any rare or adverse side effects.

3 FDA review and manufacturing (two years) – Upon successful completion of clinical trials, the company submits a New Drug Application to the FDA.

Teams of engineers, biologists, chemists and physicists work to develop ways to produce the medicine on a large scale.

SOURCE: Pharmaceutical Research and Manufacturers of America

Source: Dallasnews.com

Using an unconventional approach that they designed, University of Pittsburgh drug discoverers and their collaborators at Walter Reed Army Institute of Research have identified compounds that hold promise for treating leishmaniasis, a parasitic infection that many consider one of the world’s most overlooked diseases. The findings are available online today in PLoS Neglected Tropical Diseases.

These drug candidates, which are able to disrupt the growth of a certain stage in the life cycle of the parasite, were found by screening nearly 200,000 chemical compounds and then regrouping them into chemotypes or chemical classes, both new and known, explained senior investigator John S. Lazo, Ph.D., director of Pitt’s Drug Discovery Institute and Allegheny Foundation Professor in the Department of Pharmacology and Chemical Biology, Pitt School of Medicine. One of the most potent compounds was further tested in a mouse model of leishmaniasis to confirm it could be effective against the infection.

“We are making real progress in our effort to find new drugs to treat what I’d call the most neglected of the neglected diseases,” Dr. Lazo said. “And the method we’ve developed could be applied to find treatments for other parasitic infections, which are an enormous global health burden.”

According to the U.S. Centers for Disease Control and Prevention, each year worldwide, there are about 1.5 million new cases of cutaneous leishmaniasis skin infections, which lead to ulcers, and about 500,000 visceral infections, which lead to fever, weight loss and enlargement of the spleen and liver,. There is no vaccine or drug to prevent the parasitic infection, which is transmitted through sandfly bites.

Interest in developing new treatments for leishmaniasis has grown because of the military presence in Afghanistan and Iraq, where the infection is common, said co-investigator Col. Alan Magill, M.D., director of the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research, Silver Spring, Md.

“Our soldiers are at risk for becoming infected with the Leishmania parasite, but the treatments we have can produce serious side effects,” he said. “Also, the organism is becoming resistant to those agents, which haven’t changed in 50 years.”

For the new study, lead investigator Elizabeth R. Sharlow, Ph.D., a research assistant professor in Pitt School of Medicine’s Department of Pharmacology and Chemical Biology, took unconventional approaches to find drug candidates. First, she developed an assay based on the promastigote, the Leishmania life cycle stage that infects the sandfly, to measure the candidate’s ability to inhibit the parasite’s growth.

“Another unusual step we took was to screen compounds at relatively high concentration, which would make them more likely to affect promastigote growth,” Dr. Sharlow said. “The aim was to maximize the diversity of the active compounds, which we then clustered into similar chemotypes with powerful computational methods to make further testing more manageable.”

The researchers have dubbed this process “HILCES” for high throughput, low-stringency, computationally enhanced small molecule screening. Low stringency is the drug discovery term for high concentration.

A promising anti-leishmanial compound they found turned out to be disulfiram, or Antabuse, a drug that causes an acute sensitivity to alcohol and that is sometimes prescribed to discourage drinking among patients with chronic alcoholism. Testing in a mouse model of the infection showed that it could slow promastigote growth in a living organism, further demonstrating that the HILCES strategy can reveal effective, as well as unexpected, drug candidates.

“In a million years, we wouldn’t have thought about using a compound such as disulfiram for leishmaniasis,” noted Dr. Lazo. “It has appeal because it has already been widely used and is inexpensive, but in its current form, it might not be the best option to treat the infection. We plan to develop it further with our colleagues at Walter Reed to improve the compound’s potency and efficacy.”

All of the primary and confirmation screening data has been made available online, “so it can be data mined by medical researchers and industry anywhere in the world to identify and refine other anti-leishmanial drug candidates,” Dr. Lazo added. “And, the same screening techniques could be invaluable to find compounds to treat other parasitic infections.”

Other co-authors of the paper include David Close, B.S., Tong Ying Shun, Ph.D., Stephanie Leimgruber, M.S., Robyn Reed, M.S., all of the University of Pittsburgh Drug Discovery Institute and the Pittsburgh Molecular Library and Screening Center; Peter Wipf, Ph.D., Pitt Department of Chemistry; Gabriela Mustata, Ph.D., Department of Computational Biology, Pitt School of Medicine; and Capt. Jacob Johnson, Ph.D., Lt. Col. Michael O’Neil, Ph.D., and Col. Max Grogl, Ph.D., all of the Walter Reed Army Institute of Research.

The research was funded by grants from the U.S. Army and the National Institutes of Health.

Source: ScienceDaily (Nov. 10, 2009)

In the early 1980s, the human immunodeficiency virus (HIV) was identi­fied as the etiologic agent of acquired immune deficiency syndrome (AIDS). More than 3 million people worldwide died from HIV/AIDS in 2003, according to a July 2004 United Nations report. During the same period, about 5 million people contracted the human immunodeficiency virus, bringing the total number of people living with HIV worldwide to 38 million. Although AIDS was called the «gay men’s disease» at the be­ginning of the outbreak, it was soon discovered that sexual intercourse was not the only way of transmission. Blood transfusions and mother-to-baby transmission also spread the virus.

In comparison to the scourges caused by other viruses in history, we were more prepared and have achieved astonishing milestones against AIDS, thanks to our accumulated knowledge and efforts around the globe. HIV was identified and shown to be the cause of AIDS in less than 2% years. It took only another 2 years for blood tests to become commercially available. In 1987, the first anti-HIV drug, AZT, was introduced. With the arrival of the HIV protease inhibitors and triple drug therapy (the cocktail therapy) in 1995, many patients who would otherwise have died are still alive. In 1996, Time magazine named AIDS researcher David Ho «Man of the Year» for his revolutionary idea of the cocktail therapy.

Who discovered HIV was such a contentious is­sue that it took the President of the United States and the Premier of France to settle the dispute.

In 1983 Francoise Barre-Sinoussi and Luc Montagnier, in the laboratory led by Montagnier at the Institut Pasteur de Paris, first detected and later iso­lated a retrovirus, lymphadenopathy-associated virus (LAV), which they believed was the cause of AIDS. During their research on the virus, Montagnier’s lab­oratory collaborated with Robert C. Gallo, a renowned virologist at the National Cancer Institute (NCI), who was one of the most widely referenced scientists in the world in the 1980s and 1990s. Montagnier and Gallo frequently exchanged virus sampies and information. In April 1984, Gallo held a press conference an­nouncing that his laboratory had isolated a retrovirus, human T-lym-photrophic virus (HTLV-III), that he believed to be the cause of AIDS. Gallo was basking in scientific glory and was widely considered a leading contender for the Nobel Prize. Soon it was confirmed that Gallo’s HTLV-III and Montagnier’s LAV were identical. In 1986, a nomenclature com­mittee was set up, chaired by Harold Varmus, an expert in avian retrovirus and then director of the NIH. The NIH committee settled on the name of human immunodeficiency virus (HIV).

In April 1984, Gallo’s laboratory filed a patent on an HIV blood test kit using his HTLV-IIIB-ELISA (enzyme-linked immunosorbent assay), which was issued in a record 13 months via a special category involving na­tional security. Although Institut Pasteur had filed a patent in the United States much earlier, in December 1983, it was not granted until a later date. Gallo’s HIV test kit was approved by the FDA in 1985. An acrimonious le­gal battle ensued for the priority of the discovery of the HIV between the French and American teams. The contentious scientific and legal contro­versies came to an end in March 1987 when a historic agreement was signed by the directors of the NIH and the Institut Pasteur and ratified by Ronald Reagan and Jacques Chirac. The patents would become the joint properties of the two institutions, which would share the royalties. The three inventors from the NIH, including Gallo, would receive $100,000 annually from the royalties earned.

Even the intervention by two heads of state did not put the matter to rest. In November 1989, a Pulitzer Prize-winning investigative reporter, John Crewdson, published a 50,000-word article in the Chicago Tribune on the Montagnier-Gallo priority dispute. He concluded that Gallo had either stolen or allowed his samples to be contaminated with Montagnier’s virus. The controversy generated resulted in congressional investigations. In the end, it was found that Mikulas (Mika) Popovic from Czechoslovak­ia, a cell biologist in Gallo’s laboratory, had isolated HTLV-III from a pool by mixing several blood samples from different sources, including Montagnier’s sample, which contained LAV. Pooling blood samples was an unusual practice in virology. In 1991, Gallo admitted in Nature that he had not discovered the new virus. In 1996, he left the NCI, where he had worked for 30 years, to become the director of the Institute of Hu­man Virology at the University of Maryland Biotechnology Institute in Baltimore.

In 1987, the first anti-AIDS drug, AZT, was introduced by Burroughs Wellcome. AZT, which blocks HIV reverse transcriptase activity, stands for azidothymidine, with the generic name of zidovudine and the trade name of Retrovir. Popular media often give the credit to Gertrude Elion of Burroughs Wellcome for having discovered AZT. In fact, al­though Elion and George Hitchings (see chapter 1, page 19) developed the concept of using nucleotides as antimetabolites in treating cancers, AZT itself was synthesized by a group led by Jerome Horowitz of the Detroit Institute of Cancer Research in 1964 as a possible anticancer drug. Horowitz, now a professor at Wayne State University, published his syn­thesis as a note in the. Journal of Organic Chemistry in 1964.

Since its birth, AZT had a checkered life as a drug looking for a disease to treat. AZT did not show efficacy in treating cancers; the drug also failed to prolong the lives of leukemic animals. In 1974, a German laboratory found it effective against viral infection in mice—Wolfram Ostertag of the Max Planck Institute for Experimental Medicine showed that leukemia helper virus (LLV-F) replication by AZT occurred via phosphorylation of AZT to the corresponding triphosphate, which cannot be incorporated into the growing strand of DNA. Ostertag correctly concluded that AZT-triphosphate worked by binding to the growing strand of DNA. Bur­roughs Wellcome acquired AZT and explored the possibility of using it to treat the herpes virus under the guidance of Gertrude Elion, although it did not make it to the market.