Janet Rideout

Last updated
Janet Litster Rideout
Born (1939-01-06) January 6, 1939 (age 84)
Bennington, Vermont, USA
NationalityAmerican
Alma mater Mount Holyoke College, State University of New York, Buffalo
Known forapplication of AZT to HIV
Scientific career
Fields organic chemistry; nucleoside chemistry
Institutions Burroughs Wellcome, Inspire Pharmaceuticals

Janet Rideout is an organic chemist and one of the scientists who discovered that azidothymidine (AZT) could be used as an antiretroviral agent to treat Human Immunodeficiency Virus (HIV). [1] She also played a key role in the development of acyclovir, the first effective treatment for herpes simplex virus. [2]

Contents

Early life and education

Janet Rideout was born Janet Litster January 6, 1939, in Bennington, Vermont. She received bachelor's and master's degrees in chemistry from Mount Holyoke College. [1] She then earned a PhD in organic chemistry from State University of New York, Buffalo in 1968. [3]

Research and career

Shortly before graduation from the State University of New York, Buffalo, Rideout was hired by chemist and future Nobel laureate Gertrude Elion to work at a small US subsidiary of the British pharmaceutical company Burroughs Wellcome Company (now GlaxoSmithKline). [4] Initially located in Tuckahoe (village), New York, the branch moved to Research Triangle, North Carolina, in 1970. [5]

Rideout specialized in nucleoside chemistry. Nucelosides are chemical compounds consisting of a pentose sugar bound to a nitrogenous base. When phosphorylated, nucleosides become nucleotides, which are the building blocks of nucleic acids (DNA and RNA). [6] As such, they're needed for replication (copying of the genome before cells divide so that each gets a copy). Therefore, cells that replicate frequently, such as cancer cells and bacteria have a high demand for nucleosides. Recognizing this, teams of scientists, including a team at Burroughs Wellcome including Janet Rideout dedicated themselves to studying chemical analogs that could mimic natural nucleosides, inhibiting replication. [7]

Arabinosides

One branch of Rideout's research involved the synthesis of purine arabinosides (similar in structure to the canonical nucleosides found in DNA and RNA, but containing the sugar arabinose instead of ribose or deoxyribose). Rideout synthesized the nucleoside analog diaminopurine arabinoside, which was found to be active against herpes simplex virus and vaccinia virus and with a lower toxicity than similar compounds. [5] In her Nobel lecture, Gertrude Elion credits this finding with initiating her group's "antiviral odyssey," which would lead to the development of the HIV treatment AZT, the herpes treatment acyclovir, and other important antiretroviral compounds. [8]

The promising results from diaminopurine arabinoside led Rideout to synthesize additional purine arabinosides, in hopes of developing more effective antivirals. She worked with a team including virologists J. Bauer and P. Collins to study their pharmacological properties, discovering that aminopurine arabinosides had antiviral activity that was dependent on their amino group. [2] This knowledge helped lead to the design of more potent antiviral medications including acyclovir, the first active selective drug against herpes viruses. [2]

AZT

Rideout also studied nucleosides' antibacterial properties. One of the compounds that interested her was azidothymidine (AZT), identical to the canonical nucleoside thymidine found in DNA except for the 3' position, where AZT has an azide (N3) group instead of a hydroxyl (OH) group. That 3' OH is needed for linking nucleotides together, so AZT could potentially act as a chain terminator (it could be added to a growing nucleic acid chain, but additional nucleotides couldn't link to it). [9]

AZT was first synthesized in 1964 by a Michigan Cancer Foundation researcher, Jerome Horwitz, with hopes it could be used to treat leukemia, [5] but it wasn't found to be effective and raised toxicity concerns so it was abandoned. [10] There was limited research on it in the following years, including a report from a laboratory in showing it had activity against Friend virus, a murine virus that causes leukemia in mice, [7] but retroviruses weren't thought to affect humans, and the paper drew little attention. [11]

Rideout was interested in AZT's other potential applications; she studied AZT as an antibacterial agent at the Burroughs Wellcome Company for several years. [12] The compound was particularly effective against gram-negative bacteria. [13] In addition to chemical characterization and optimization of its synthesis, their research included pharmacokinetic and safety testing in rats. [14] This experience, and the data they collected showing that the drug was tolerated in rats placed them in a prime position to expedite the drug development process. [5] [14]

In June 1984, Burroughs Wellcome initiated a program to identify chemical compounds that might be effective against HIV, and they put Rideout in charge of choosing which compounds to test. [5] There was limited knowledge about HIV at the time, but Rideout's search was aided by the finding that HIV was a retrovirus, a type of virus that transfers between cells with its genome encoded in RNA but, once it infects a host cell, reverse transcribes its RNA genome into a DNA copy which it then inserts into the host cell's DNA, so that the cell and all its progeny are perpetually infected. Knowing that HIV was a retrovirus, Rideout searched for compounds with antiretroviral activity; the company didn't have the necessary set-up for studying live HIV, so they screened against animal retroviruses, [15] with the screening carried out by virologist Martha (Marty) St. Clair. [11]

One of the compounds Rideout chose to test was AZT and by the end of 1984, Wellcome had shown that AZT was active against two animal retroviruses, Harvey sarcoma virus and Friend leukemia virus. [5] To see if it was also active against HIV, they collaborated with scientists at the National Cancer Institute (NCI), including Samuel Broder and Hiroaka Mitsuya, who had developed a method to grow the virus in immortalized human T4 cells (the type of immune cell HIV targets). [14] NCI found AZT to be highly effective against HIV in these cells, [5] and it went on to become the first FDA-approved treatment for HIV.

In 1985, Rideout, along with four other BW scientists, applied for American and British patents for the use of AZT, given the chemical name zidovudine and the proprietary name Retrovir, for the treatment of HIV-1; they were approved in 1988, with Rideout is listed as the first co-inventor. [7]

Rideout's research on AZT didn't stop with its initial application to HIV. In the coming years at Burroughs Wellcome, she helped elucidate how AZT is processed in the body (administered as the cell membrane-permeable nucleoside, it is phosphorylated inside cells to the nucleotide form which is used in DNA synthesis) and how it selectively targets HIV's reverse transcriptase. [16] She also continued to look into AZT's other potential uses, including against other viruses and bacteria. [17]

Later career

In 1995, after working at Burroughs Wellcome for over 26 years, and rising to the rank of associate division director, Rideout joined Inspire Pharmaceuticals (acquired by Merck in 2011) [18] as Director of Chemistry. [3] She subsequently had a number of promotions within the company: to Senior Director of Discovery in June 1996, Vice President in January 1998, and Senior Vice President of Discovery in February 2000. [3]

At Inspire Pharmaceuticals, she continued researching nucelosides but now as activators (agonists) instead of inhibitors. In addition to their role in the biosynthesis of nucleic acids, nucleotides can serve as important signaling molecules including through activating purinergic receptors. Rideout helped develop ways to synthesize a type of purinergic receptor agonist called dinucleoside polyphosphates (dinucleotides), which consist of two joined nucleosides with varying numbers of phosphate groups, so they can be further studied. [19]

Rideout retired in September 2000. [20]

Rideout holds over 40 U.S. patents. [21] In addition to the patent for treating HIV with AZT, she holds patents for synthesis procedures of various nucleoside analogs as well as their specific therapeutic applications; this includes derivatives of AZT for use treating and preventing infection by certain retroviruses and gram-negative bacteria. [13]

Honors and awards

Selected publications

Related Research Articles

<span class="mw-page-title-main">Antiviral drug</span> Medication used to treat a viral infection

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.

<span class="mw-page-title-main">Thymidine</span> Chemical compound

Thymidine, also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. In cell biology it is used to synchronize the cells in G1/early S phase. The prefix deoxy- is often left out since there are no precursors of thymine nucleotides involved in RNA synthesis.

<span class="mw-page-title-main">Zidovudine</span> Antiretroviral medication

Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.

<span class="mw-page-title-main">Gertrude B. Elion</span> American biochemist and pharmacologist (1918–1999)

Gertrude "Trudy"Belle Elion was an American biochemist and pharmacologist, who shared the 1988 Nobel Prize in Physiology or Medicine with George H. Hitchings and Sir James Black for their use of innovative methods of rational drug design for the development of new drugs. This new method focused on understanding the target of the drug rather than simply using trial-and-error. Her work led to the creation of the anti-retroviral drug AZT, which was the first drug widely used against AIDS. Her well known works also include the development of the first immunosuppressive drug, azathioprine, used to fight rejection in organ transplants, and the first successful antiviral drug, acyclovir (ACV), used in the treatment of herpes infection.

<span class="mw-page-title-main">Aciclovir</span> Antiviral medication used against herpes, chickenpox and shingles

Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Thymidine kinase</span> Enzyme found in most living cells

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

<span class="mw-page-title-main">Vidarabine</span> Chemical compound

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Foscarnet</span> Chemical compound

Foscarnet (phosphonomethanoic acid), known by its brand name Foscavir, is an antiviral medication which is primarily used to treat viral infections involving the Herpesviridae family. It is classified as a pyrophosphate analog DNA polymerase inhibitor. Foscarnet is the conjugate base of a chemical compound with the formula HO2CPO3H2 (Trisodium phosphonoformate).

<span class="mw-page-title-main">Deoxyguanosine triphosphate</span> Chemical compound

Deoxyguanosine triphosphate (dGTP) is a nucleoside triphosphate, and a nucleotide precursor used in cells for DNA synthesis. The substance is used in the polymerase chain reaction technique, in sequencing, and in cloning. It is also the competitor of inhibition onset by acyclovir in the treatment of HSV virus.

<span class="mw-page-title-main">Resistance mutation (virology)</span> Virus mutation

A resistance mutation is a mutation in a virus gene that allows the virus to become resistant to treatment with a particular antiviral drug. The term was first used in the management of HIV, the first virus in which genome sequencing was routinely used to look for drug resistance. At the time of infection, a virus will infect and begin to replicate within a preliminary cell. As subsequent cells are infected, random mutations will occur in the viral genome. When these mutations begin to accumulate, antiviral methods will kill the wild type strain, but will not be able to kill one or many mutated forms of the original virus. At this point a resistance mutation has occurred because the new strain of virus is now resistant to the antiviral treatment that would have killed the original virus. Resistance mutations are evident and widely studied in HIV due to its high rate of mutation and prevalence in the general population. Resistance mutation is now studied in bacteriology and parasitology.

<span class="mw-page-title-main">Sorivudine</span> Chemical compound

Sorivudine (INN), is a nucleoside analogue antiviral drug, marketed under trade names such as Usevir and Brovavir (BMS). It is used for the treatment of varicella zoster virus infections.

<span class="mw-page-title-main">Thymidine kinase from herpesvirus</span>

Thymidine kinase from herpesvirus is a sub-family of thymidine kinases that catalyses the transfer of phospho group of ATP to thymidine to generate thymidine monophosphate, which serves as a substrate during viral DNA replication.

<span class="mw-page-title-main">Herpes simplex</span> Viral disease caused by herpes simplex viruses

Herpes simplex, often known simply as herpes, is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Pritelivir</span> Chemical compound

Pritelivir is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. Pritelivir is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG.

<span class="mw-page-title-main">Protide</span>

The ProTide technology is a prodrug approach used in molecular biology and drug design. It is designed to deliver nucleotide analogues into the cell. This technology was invented by Professor Chris McGuigan from the School of Pharmacy and Pharmaceutical Sciences at Cardiff University in the early 1990s. ProTides form a critical part of antiviral drugs such as sofosbuvir, tenofovir alafenamide, and remdesivir.

<span class="mw-page-title-main">Carbocyclic nucleoside</span> Class of chemical compounds

Carbocyclic nucleosides are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

References

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  15. ↑ "BURROUGHS WELLCOME v. BARR LABORATORIES, 828 F. Supp. 1208 | Casetext". casetext.com. Retrieved 2018-09-16.
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  17. ↑ Elwell, L. P.; Ferone, R.; Freeman, G. A.; Fyfe, J. A.; Hill, J. A.; Ray, P. H.; Richards, C. A.; Singer, S. C.; Knick, V. B. (1987-02-01). "Antibacterial activity and mechanism of action of 3'-azido-3'-deoxythymidine (BW A509U)". Antimicrobial Agents and Chemotherapy. 31 (2): 274–280. doi:10.1128/AAC.31.2.274. ISSN   0066-4804. PMC   174705 . PMID   3551832.
  18. ↑ Reuters Editorial. "Merck to acquire Inspire Pharma for $430 million". U.S. Retrieved 2018-09-19.{{cite news}}: |author= has generic name (help)
  19. ↑ Shaver, Sammy R.; Rideout, Janet L.; Pendergast, William; Douglass, James G.; Brown, Edward G.; Boyer, José L.; Patel, Roshni I.; Redick, Catherine C.; Jones, Arthur C. (2005-03-07). "Structure–activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors". Purinergic Signalling. 1 (2): 183–191. doi:10.1007/s11302-005-0648-2. ISSN   1573-9546. PMC   2096529 . PMID   18404503.
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  22. ↑ "Alumni Awards - College of Arts and Sciences - University at Buffalo". arts-sciences.buffalo.edu. Retrieved 2018-09-19.
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