Acyclovir for the Treatment of Herpes

Acyclovir is an antiviral medication that scientists developed in the twentieth century to treat herpes, a disease caused by the viruses herpes simplex virus-1 and herpes simplex virus-2, or HSV-1 and HSV-2. The viruses cause painful lesions to develop on the mouth and genitals. Herpes is a very common condition and acyclovir was one of the first medications to effectively heal and reduce the duration of lesions caused by HSV-1 and HSV-2. Scientists at Wellcome Research Laboratories in Research Triangle Park, North Carolina, developed acyclovir with the specific aim of inhibiting the replication process of HSV-1 and HSV-2 in a host’s cell, which was a novel approach to drug development at the time. Physicians have since used acyclovir to treat other diseases caused by herpesviruses. Scientists have developed new drugs for the treatment of genital herpes based on acyclovir’s mechanism of action and, as of 2024, physicians still prescribe acyclovir to treat oral and genital herpes, providing relief to the millions of people living with herpes globally.

1. What Is Herpes?
2. History of Herpes
3. The Development of Acyclovir
4. The Mechanism of Acyclovir for Herpes Treatment
5. Further Research on Acyclovir and Herpes
6. Acyclovir in the Decades After Its Invention
7. The Social Impact of Acyclovir

What Is Herpes?

Herpes is one of the most common viral infections globally. The World Health Organization, or WHO, estimated that in 2016, 3.7 billion people, or sixty-seven percent of people under the age of fifty globally, have HSV-1. WHO also estimated that in 2016, 491 million or thirteen percent of people between the ages of fifteen and forty-nine globally had HSV-2.

Populations all around the world suffer from HSV-1 and HSV-2 at high rates due to the virus’s mode of transmission. People can contract herpes via close contact or sexual contact, such as sharing eating utensils, kissing, or any kind of sexual activity. HSV-1 can cause oral lesions on the mouth, called cold sores, and genital lesions, while HSV-2 most commonly causes genital lesions. An individual can have both HSV-1 and HSV-2.

Once a person contracts herpes, they can experience both initial and recurring outbreaks of lesions. Initial outbreaks of genital herpes are often more painful and take longer to fully heal than the following recurrent outbreaks. Initial outbreaks can last two to three weeks, causing itching, discomfort, painful urination, and flu-like symptoms during that time. Most people experience recurrent outbreaks after an initial episode of genital herpes. One or multiple recurrent episodes can happen during the first year of infection, and then episodes typically decrease in frequency over time. Recurrent episodes are usually much less severe in terms of symptoms and duration than the initial episode. Prior to a recurrent episode, many people experience prodromes, which are early symptoms such as genital pain or tingling sensations that occur in the legs, buttocks, or hips, that indicate an incipient outbreak. Those prodromal symptoms occur a few hours or days before an episode of genital herpes. Sometimes people can predict they will have an outbreak when prodromes occur, and they can then begin taking antiviral medications to prevent or minimize the outbreak.

History of Herpes

Despite the widespread occurrence of herpes, it was highly stigmatized in the late twentieth century. In 1980, Time magazine published an article titled “Herpes: The New Sexual Leprosy.” By calling herpes “the new sexual leprosy,” Time likened herpes to leprosy, a long-term, progressive bacterial infection that causes discoloration, skin flaking, inflammation, nerve damage and more. Historically, leprosy was an extremely stigmatized disease. In fact, families of people with leprosy disowned their afflicted loved ones and banished them to isolated leper colonies up until the mid-twentieth century. Just two years later, in 1982, Time published “The New Scarlet Letter.” In that article, Time referred to people with genital herpes as herpetics, and the author details the negative sexual and relationship experiences of people with herpes as a result of their infection, further promoting the stigmatization of individuals with the disease.

Herpes was largely untreatable before the development of acyclovir. In “Herpes: The New Sexual Leprosy,” Time describes how researchers and those suffering with herpes tried to cure cases of the disease using supplements, including vitamin C, zinc, and fluorescent light. A 1982 New York Times article, “The Herpes Syndrome,” describes even more home remedies and therapies used by people to try to treat herpes, such as acupuncture, applying yogurt, red seaweed, and cold milk compresses to genital lesions, and more. Another New York Times article from 1976 titled “Viruses of Love” details other herpes treatments from the time including burning herpes lesions with electrical currents, applying ether, which is a highly flammable liquid commonly used as an anesthetic, to lesions, and taking idoxuridine, an antiviral drug created in the early 1960s. Though idoxuridine is an antiviral drug like acyclovir, it is most effective at treating herpes infections of the eye and is primarily used for that purpose. Researchers found that idoxuridine does not reduce the duration of lesions, it may be toxic, and it also causes burning and skin inflammation when applied to oral or genital herpes. The medication and home remedies people used in the twentieth century for herpes were neither safe nor effective, so there was a need for a drug that effectively treats herpes.

The Development of Acyclovir

Researchers at Wellcome Research Laboratories, called GlaxoSmithKline as of 2024, created acyclovir using a new, methodical approach to drug development that included making a compound similar to a component of DNA that inhibited viral DNA replication. Beginning in the mid-twentieth century, scientists sought to treat diseases by engineering medications that could interfere with the replication process of disease-causing pathogens including viruses, bacteria, fungi, and even cancer. Viruses, a specific type of pathogen primarily consisting of genetic material inside of a protein envelope, replicate inside of an organism’s cells and use the host’s cellular machinery to reproduce, making more copies of itself. Acyclovir was developed specifically to interfere with the DNA replication of HSV.

Beginning in the late 1960s, researchers at Wellcome Research Laboratories spent decades making chemical compounds that could imitate nucleosides, which are the component of DNA containing a nitrogenous base and a five-carbon sugar, in an attempt to interrupt the replication cycle of targeted pathogens. Scientists synthesized chemical compounds called nucleoside analogues, which are structures similar to DNA nucleosides, that could inhibit DNA replication by inserting themselves into the viral DNA chain where a nucleotide would usually go. However, the synthesized nucleosides are not capable of linking with the next nucleotide, thereby preventing the viral DNA chain from growing further. Nucleotides are the building blocks of DNA, containing a sugar molecule, a phosphate molecule, and a nitrogenous base, such as adenine or guanine. Nucleotides link together to form chains of DNA.

Around the same time as Wellcome researchers were developing synthetic nucleosides, many scientists were attempting to create antiviral drugs for the treatment of viral diseases, like herpes. According to Gertrude Elion, one of the inventors of acyclovir, at that time in the mid-twentieth century, the scientific community largely believed that it was not possible to prevent a virus from replicating inside of a host’s cells without damaging the host’s DNA. But in 1968, researcher Frank M. Schabel published an article claiming that the compound adenine arabinoside, a nucleoside analogue that imitates the nitrogenous base adenine, had demonstrated antiviral behaviors against DNA viruses including HSV. In his report, Schabel calls adenine arabinoside a potentially useful antiviral agent and says that adenine arabinoside’s therapeutic activity warranted clinical trials investigating the compound’s use in humans. Schabel’s report led Elion and the other scientists and Wellcome Research Laboratories to reexamine a previously synthesized analogue compound, 2,6-diaminopurine. Elion and the others revisited 2,6-diaminopurine because they had previously noticed the compound had antiviral activity against another DNA virus and it closely resembled adenine in structure. So, the research team refined 2,6-diaminopurine into 2,6-diaminopurine arabinoside, or Ara-DAP, an adenine nucleoside analogue, to see if Ara-DAP had antiviral activity.

In the late 1960s, Wellcome Research Laboratories scientists continued to work with Ara-Dap, conducting research to see if the compound had antiviral properties against viruses like HSV. In 1969, Elion and colleagues sent that compound to their colleague John Bauer, a researcher at Wellcome Research Laboratories in the United Kingdom who ran a virus laboratory. Bauer found that Ara-DAP had antiviral activity against HSV-1 and HSV-2. According to Elion, the discovery of Ara-DAP’s HSV inhibiting activity encouraged the Wellcome Research scientists to expand their search for antiviral compounds to include other compounds that were similar to Ara-DAP. They studied the structure of compounds and they conducted metabolic studies in mice to try to identify more compounds with antiviral properties. Then, in the 1970s, the antiviral program at Wellcome Research Laboratories began to concentrate on the work of its scientists Howard Schaeffer and Lillia Beauchamp who synthesized 2,6-diamino-9-(2-hydroxyethoxymethyl) purine, later named acyclovir, which was 100 times more active, in terms of inhibiting viral replication, than the previous adenine-based compound. That compound was a guanine analogue, mimicking a nitrogenous base in DNA. In an autobiographical article, "The Quest for a Cure," published in 1993, Elion describes the discovery of acyclovir as incredibly exciting to her research team and she says they then set out to refine the compound to turn it into a drug capable of treating HSV.

The Mechanism of Acyclovir for Herpes Treatment

Acyclovir effectively targets and interrupts the replication process of HSV without damaging the host’s cells. HSV consists of a protein envelope with viral DNA inside. HSV uses those proteins on its envelope to fuse with a host’s cells and the viral DNA is delivered to the cytoplasm and transported to the host cell’s nucleus. From there, HSV begins to go through the DNA synthesis process in the nucleus using the host’s cellular machinery. For HSV to replicate properly, viral polymerase, an enzyme that carries out multiple functions in the process of viral DNA synthesis, must be functioning properly. When acyclovir enters a cell, a viral enzyme abundant in infected cells activates the drug. Activated acyclovir, known as acyclovir triphosphate, inhibits the viral replication process of HSV-1 and HSV-2, and other herpesviruses by binding to the viral polymerase molecule. Because acyclovir triphosphate is structurally similar to deoxyguanosine triphosphate, a nucleotide that is a building block of DNA, the viral polymerase molecule inserts the activated acyclovir into the growing chain of DNA. Active acyclovir lacks a crucial chemical compound required to add the next nucleotide in the DNA chain. So, when acyclovir enters the DNA chain, it halts the growing chain, preventing further viral DNA synthesis and replication. Due to its activation by viral enzymes and mechanism of action, acyclovir is highly specific, meaning that it is very efficient at inhibiting the replication process of HSV in host cells without harming other cells or cellular structures. That ability is crucial because HSV replicates inside of host cells and uses the cell’s machinery to produce the viral genetic material. So, any compound that can affect the virus could also affect the genetic material of the host cell. Host cells’ DNA polymerase has a lower affinity for the active acyclovir compared to the viral DNA polymerase, so acyclovir does not harm them.

Further Research on Acyclovir and Herpes

During the 1970s, the Wellcome research team conducted numerous mechanistic and metabolic studies of acyclovir to determine the byproducts of acyclovir and the mechanisms that made it so effective. During those years, the research team also conducted experiments on animals to learn about the toxicity, effectiveness, and metabolic process of acyclovir in a host. In 1977 and 1978, they published two academic papers in the journals Proceedings of the National Academy of Sciences and Nature about their findings regarding how well acyclovir performed in animal models and the mechanisms by which it inhibited viral replication. The 1977 article reports on acyclovir’s high degree of specificity for HSV and its affinity for viral polymerase. In the 1978 Nature article, the researchers explain that acyclovir ointment reduced the duration of lesions in guinea pigs infected with HSV-1 and had low toxicity. Many other researchers at Wellcome Research Laboratories and other institutions researched acyclovir and its mechanisms of action and uses during the late 1970s as well.

In 1981, Burroughs Wellcome Company and the US National Institute of Allergy and Infectious Disease hosted a three-day conference about acyclovir, with seventy-seven paper presentations and fifty-two lectures about acyclovir, its chemical makeup, the mechanisms that make the drug effective, the results of animal experiments that used the drug, and more. The American Journal of Medicine published the proceedings of the symposium, in which one physician described the development of acyclovir as a novel and exciting therapeutic agent with a unique mode of action and safety parameters. The acyclovir symposium was an international event where researchers from various institutions gathered to discuss the findings of their research on acyclovir and how acyclovir could be used in clinical settings to treat HSV-1, HSV-2, and other herpesviruses, and what the creation and use of acyclovir meant for the future of drug development.

Throughout the rest of the 1980s, researchers continued to study acyclovir, and the US Food and Drug Administration, or FDA, approved the drug for public use. Following the acyclovir symposium, in 1982, physician Lawrence Corey conducted human clinical trials and found that when participants experiencing initial or recurrent outbreaks of genital herpes took idoxuridine, an antiviral similar to acyclovir, the healing time of lesions was not significantly shorter than placebo group participants who did not take idoxuridine. Later that year, the FDA approved acyclovir ointment and an intravenous formulation only for the treatment of initial outbreaks of herpes under the brand name Zovirax. But after FDA approval for public use, sales of acyclovir fell short of expectations according to the New York Times. The newspaper described Zovirax’s market performance as lackluster in a 1983 article. The article explains that the FDA had only approved the ointment for treatment of initial, not recurring, outbreaks, and they speculated that the limitation may have been responsible for the medication’s low profits. In 1985, however, the FDA approved an oral formulation of acyclovir, which was extremely effective at treating initial and recurrent outbreaks. In 1997, the World Health Organization, or WHO, listed acyclovir on the WHO Model List of Essential Medicines for the treatment of herpes simplex infections.

Acyclovir in the Decades After Its Invention

The patent for Zovirax, the brand name for acyclovir, expired in 2007 and many other pharmaceutical companies began to manufacture the medication, producing generic versions, making the medication more affordable. As of 2024, physicians still use acyclovir to treat HSV-1 and HSV-2, as well as other viruses in the herpes family. According to the US Centers for Disease Control and Prevention, treatment for individuals experiencing an initial outbreak of genital herpes is 400 mg of acyclovir by mouth three times per day for seven to ten days. Suppressive therapy for the prevention of future outbreaks and decreased transmissibility is 400 mg of acyclovir by mouth twice daily. Episodic therapy for the treatment of a recurrent episode of herpes lesions must be initiated within one day of a lesion’s appearance or when the person begins to experience prodromal symptoms, the tingling, burning, or itching pain that predates an outbreak. The recommended regimen for episodic therapy is 800 mg by mouth twice daily for five days or 800 mg by mouth thrice daily for two days. According to ClinCalc, in 2021, acyclovir was prescribed over three million times in the US and was ranked 169 on a list of most commonly prescribed drugs.

The Social Impact of Acyclovir

The creation of acyclovir led to the development of other nucleoside analogue drugs to treat genital herpes as well as another virus in the herpes family that causes shingles. Elion and George Hitchings won the Nobel Prize in Physiology or Medicine in 1988 for their contributions to the field of pharmacology, namely for their novel method of drug development, in which they targeted the differences in pathogen DNA and human DNA to develop safe and effective medications. In 1995, the FDA approved valacyclovir for public use. Valacyclovir is a prodrug, meaning it is converted into acyclovir in the body after being ingested. Structurally, valacyclovir is identical to acyclovir except for the addition of the amino acid valine. Valacyclovir has a longer duration of action and so it be taken fewer times a day compared to acyclovir. Valacyclovir, however, tends to be more expensive than acyclovir. Acyclovir has also inspired the development of famciclovir, a similar drug frequently used to treat shingles, a painful rash caused by the varicella zoster virus, or chickenpox virus, which is another herpesvirus. The development of acyclovir not only produced a safe and effective treatment for HSV but contributed knowledge to the field of pharmacology regarding ways to develop medications that specifically kill pathogens and do not harm the host.