Janet Rideout is an
organic chemist
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
and one of the scientists who discovered that
azidothymidine
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 ...
(AZT) could be used as an antiretroviral agent to treat
Human Immunodeficiency Virus (HIV).
She also played a key role in the development of
acyclovir
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 tran ...
, the first effective treatment for
herpes simplex virus
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
.
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
Mount Holyoke College is a private liberal arts women's college in South Hadley, Massachusetts. It is the oldest member of the historic Seven Sisters colleges, a group of elite historically women's colleges in the Northeastern United States.
...
.
She then earned a PhD in organic chemistry from
State University of New York, Buffalo in 1968.
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
Gertrude "Trudy" Belle Elion (January 23, 1918 – February 21, 1999) 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 innovat ...
to work at a small US subsidiary of the British pharmaceutical company
Burroughs Wellcome Company (now GlaxoSmithKline). Initially located in
Tuckahoe (village), New York
Tuckahoe is a village in Westchester County, New York, United States. One-and-a-half miles long and three-fourths of a mile wide, with the Bronx River serving as its western boundary, the Village of Tuckahoe is approximately sixteen miles north ...
, the branch moved to
Research Triangle, North Carolina
The Research Triangle, or simply The Triangle, are both common nicknames for a metropolitan area in the Piedmont region of North Carolina in the United States, anchored by the cities of Raleigh and Durham and the town of Chapel Hill, home to t ...
in 1970.
Rideout specialized in
nucleoside
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
chemistry. Nucelosides are chemical compounds consisting of a
pentose
In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atoms. The chemical formula of many pentoses is , and their molecular weight is 150.13 g/mol.[nitrogenous base
Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...]
. When
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
, nucleosides become
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
s, which are the building blocks of
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
s (
DNA and
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
). 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.
Arabinosides
One branch of Rideout's research involved the synthesis of
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
arabinosides
Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group.
For biosynthetic reasons, most saccharides are almost always more abundant in nature as the "D"-form, or structural ...
(similar in structure to the canonical
nucleoside
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
s found in DNA and RNA, but containing the sugar
arabinose
Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group.
For biosynthetic reasons, most saccharides are almost always more abundant in nature as the "D"-form, or structurally ...
instead of
ribose
Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this compo ...
or
deoxyribose
Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...
). Rideout synthesized the nucleoside analog diaminopurine arabinoside, which was found to be active against
herpes simplex virus
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
and
vaccinia virus
''Vaccinia virus'' (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...
and with a lower toxicity than similar compounds.
In her Nobel lecture,
Gertrude Elion
Gertrude "Trudy" Belle Elion (January 23, 1918 – February 21, 1999) 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 innovat ...
credits this finding with initiating her group's "antiviral odyssey," which would lead to the development of the
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
treatment
AZT
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 ...
, the
herpes
Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.
Oral herpes involves the face or mouth. It may result in small blisters in groups often called cold s ...
treatment
acyclovir
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 tran ...
, and other important
antiretroviral
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multipl ...
compounds.
The promising results from diaminopurine arabinoside led Rideout to synthesize additional purine arabinosides, in hopes of developing more effective
antivirals
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. Unlike most antibiotics, antiviral drugs do no ...
. 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.
This knowledge helped lead to the design of more potent antiviral medications including
acyclovir
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 tran ...
, the first active selective drug against
herpes
Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.
Oral herpes involves the face or mouth. It may result in small blisters in groups often called cold s ...
viruses.
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).
AZT was first synthesized in 1964 by a Michigan Cancer Foundation researcher,
Jerome Horwitz
Jerome Phillip Horwitz (January 16, 1919 – September 6, 2012) was an American scientist; his affiliations included the Barbara Ann Karmanos Cancer Institute, the Wayne State University School of Medicine and the Michigan Cancer Foundation.
...
, with hopes it could be used to treat
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
,
but it wasn't found to be effective and raised toxicity concerns so it was abandoned.
There was limited research on it in the following years, including a report from a laboratory in showing it had activity against
Friend virus
The Friend virus (FV) is a strain of murine leukemia virus identified by Charlotte Friend in 1957. The virus infects adult immunocompetent mice and is a well-established model for studying genetic resistance to infection by an immunosuppressive ...
, a murine virus that causes leukemia in mice,
but retroviruses weren't thought to affect humans, and the paper drew little attention.
Rideout was interested in AZT's other potential applications; she studied AZT as an antibacterial agent at the Burroughs Wellcome Company for several years. The compound was particularly effective against
gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
.
In addition to chemical characterization and optimization of its synthesis, their research included pharmacokinetic and safety testing in rats.
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.
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.
There was limited knowledge about HIV at the time, but Rideout's search was aided by the finding that HIV was a
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
, 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, with the screening carried out by virologist Martha (Marty) St. Clair.
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.
To see if it was also active against HIV, they collaborated with scientists at the
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
(NCI), including
Samuel Broder
Samuel Broder spent his childhood in Poland, in a group of Jewish guerrillas threatened by the Nazis. He emigrated to the United States with a group of Polish survivors and settled with his parents in an industrial neighborhood in Detroit, where ...
and
Hiroaka Mitsuya, who had developed a method to grow the virus in immortalized human
T4 cells (the type of immune cell HIV targets).
NCI found AZT to be highly effective against HIV in these cells,
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.
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
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
, it is
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
inside cells to the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
form which is used in DNA synthesis) and how it selectively targets HIV's
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
.
She also continued to look into AZT's other potential uses, including against other viruses and bacteria.
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
Merck refers primarily to the German Merck family and three companies founded by the family, including:
* the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668
** Merck Serono (known as EMD Serono in the Unite ...
in 2011) as Director of Chemistry.
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.
At Inspire Pharmaceuticals, she continued researching nucelosides but now as activators (
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s) instead of inhibitors. In addition to their role in the biosynthesis of
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
s, nucleotides can serve as important signaling molecules including through activating
purinergic receptor
Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, lo ...
s. 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.
Rideout retired in September 2000.
Rideout holds over 40 U.S. patents.
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
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
es and
gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
.
Honors and awards
* Distinguished Chemist award, North Carolina Institute of Chemists, 1994
* Dean's Award,
State University of New York, Buffalo, College of Arts and Science, 2012
*
State University of New York, Buffalo Alumni Association, Distinguished Alumni Award, March 2014
* Life fellow and member of board of directors,
American Institute of Chemists
The American Institute of Chemists (AIC) is an organization founded in 1923 with the goal of advancing the chemistry profession in the United States. The institute is known for its yearly awards recognizing contributions of individuals in this fi ...
Selected publications
*
*
References
{{DEFAULTSORT:Rideout, Janet Litster
American pharmacologists
Women pharmacologists
American women biochemists
21st-century American chemists
21st-century American women scientists
American women chemists
1939 births
Living people
University at Buffalo alumni
Mount Holyoke College alumni