Antifungal Drugs
Because the cells of fungi are eukaryotic, they present special problems in chemotherapy. The great majority of chemotherapeutic drugs are designed to act on bacteria and are generally ineffective in combating fungal infections. And because fungal and human cells are so similar, drugs toxic to fungal cells are also capable of harming human tissues. A few agents with special antifungal properties have been developed for treating fungal infections. The main drug groups currently in use are the macrolide polyene antibiotics, griseofulvin, synthetic azoles, flucytosine, echinocandins, and fungerps (figure 1).
Fig1. Some antifungal drug structures. (a) Polyenes. The example shown is amphotericin B, a complex steroidal antibiotic that inserts into fungal cell membranes. (b) Azoles, complex cyclic (ringed) compounds, such as ketoconazole, which inhibits synthesis of ergosterol, a component of the fungal cell membrane. (c) Flucytosine, a structural analog of cytosine that inhibits DNA and protein synthesis.
Polyenes bind to fungal membranes and cause loss of selective permeability. They are specific for fungal membranes because fun gal membranes contain a particular sterol component called ergosterol, which human membranes do not contain. The toxicity of polyenes is not completely selective, however, because mammalian cell membranes contain compounds similar to ergosterol that bind polyenes to a small extent.
Macrolide polyenes, represented by amphotericin B (Fungi zone) (named for its acidic and basic—amphoteric—properties) and nystatin (for New York State, where it was discovered), have a structure that mimics the lipids in some cell membranes. Amphotericin B is by far the most versatile and effective of all antifungals. Not only does it work on most fungal infections, including skin and mucous membrane lesions caused by Candida albicans, but it is one of the few drugs that can be injected to treat systemic fungal infections such as histoplasmosis and cryptococcus meningitis. A significant drawback to the widespread use of amphotericin centers on its serious side effects, which can include fatigue and irregular heartbeat. Nystatin (Mycostatin) is used only topically or orally to treat mycoses of the skin and mucous membranes, but it is not useful for subcutaneous or systemic fungal infections or for ringworm.
Griseofulvin is an antifungal product especially active in treating certain dermatophyte infections such as athlete’s foot. The drug is deposited in the epidermis, nails, and hair, where it inhibits fungal growth. Because complete eradication requires several months and griseofulvin is relatively nephrotoxic, this therapy is given only for the most stubborn cases. A newer drug for treatment of ringworm and athlete’s foot, terbinifine (Lamisil), is an inhibitor of ergosterol synthesis that is readily deposited in skin and nails. Unfortunately, it must also be taken for an extended period and has a number of side effects, including hepatotoxicity.
The azoles are broad-spectrum antifungal agents with a complex ringed structure that also inhibits ergosterol and cell membrane synthesis. They have fewer adverse side effects when compared with other antifungal drugs. The most effective drugs are ketoconazole (Nizoral), fluconazole (Diflucan), clotrimazole (Gyne-Lotrimin), miconazole (Monistat), voriconazole (VFEND), and itraconazole (Sporanox). Ketoconazole is used orally and topically for cutaneous mycoses, vaginal and oral candidiasis, and some systemic and invasive mycoses. Fluconazole can be used in selected patients for AIDS-related mycoses such as aspergillosis and cryptococcus meningitis. Clotrimazole and miconazole are used mainly as topical ointments for infections in the skin, mouth, and vagina. Itraconazole is generally used orally for fungal infections of the nails and systemic candidiasis. Because voriconazole crosses the blood-brain barrier, it is the treatment of choice for fungal meningitis. A new member of the azole family, Cresemba, is designated for severe systemic mycoses such as aspergillosis and mucormycosis.
Flucytosine is an analog of the nucleotide cytosine that has antifungal properties. It is rapidly absorbed after oral therapy, and it is readily dissolved in the blood and cerebrospinal fluid. Alone, it can be used to treat certain cutaneous mycoses. Many fungi are resistant to flucytosine, so it is usually combined with amphotericin B to effectively treat systemic mycoses.
Echinocandins, such as Caspofungin, damage the cell walls of several types of fungi, thereby making them sensitive to lysis. A significant advantage of this mode of action is that it cannot target human cells.
Fungerps represent the first new class of antifungal drug in 20 years. This class, which so far includes only a single drug (ibrexafungerp) works by inhibiting the synthesis of glucans needed for synthesis of the fungal cell wall. The drug is targeted at Candida species that have evolved resistance to azoles and echinoderms, and it can be taken orally, greatly simplifying administration.
Antiparasitic Chemotherapy
The enormous diversity among protozoan and helminth parasites and their corresponding therapies reaches far beyond the scope of this textbook; however, a few of the more common drugs are surveyed here. Presently a small number of approved and experimental drugs are used to treat malaria, leishmaniasis, trypanosomiasis, amebic dysentery, and helminth infections, but the need for new and better drugs has spurred considerable research in this area.
Antimalarial Drugs: Quinine and Its Relatives
Quinine, a toxic chemical extracted from the bark of the cinchona tree, was the principal treatment for malaria for hundreds of years, but it has largely been replaced by the synthesized quinolines, mainly chloroquine and primaquine, which have less toxicity to humans. Because of the several species of Plasmodium (the malaria parasite) and many stages in its life cycle, no single drug is universally effective for every species and stage, and each drug is restricted in application. For instance, primaquine eliminates the liver phase of infection, and chloroquine suppresses acute attacks associated with infection of red blood cells. It is also given as a prophylactic treatment in endemic regions. Chloroquine is usually taken in combination with another drug to reduce the chances of parasite resistance.
Mefloquine is a semisynthetic analog of quinine used to treat infections caused by chloroquine-resistant strains of Plasmodium, an increasing problem in Southeast Asia. The latest drug approved for treating uncomplicated malaria is a combination of artimisinin and lumefantrine called Coartem. It was designed to prevent drug resistance and has become the drug of choice in many parts of the world.
Chemotherapy for Other Protozoan Infections
A widely used amoebicide, metronidazole (Flagyl), is effective in treating intestinal infections and hepatic disease caused by Entamoeba histolytica. It appears to inactivate essential metabolic enzymes of the pathogens. Given orally, it also has applications for infections by Giardia lamblia and Trichomonas vaginalis. Other drugs with antiprotozoan activities are quinacrine (a quinine-based drug), sulfonamides, and tetracyclines.
Antihelminthic Drug Therapy
Treating helminthic infections has been one of the most challenging of all chemotherapeutic tasks. Flukes, tapeworms, and roundworms are much larger parasites than other microorganisms and, being animals, have greater similarities to human physiology. Also, the usual strategy of using drugs to block their reproduction is usually not successful in eradicating the adult worms. The most effective drugs immobilize, disintegrate, or inhibit the metabolism of all stages of the life cycle.
Mebendazole and albendazole are broad-spectrum antiparasitic drugs used to treat several types of roundworm infections. These drugs work locally in the intestine to inhibit the function of the microtubules of worms, eggs, and larvae, which blocks a key step in glucose metabolism and disables them. The compounds pyrantel and praziquantel paralyze the muscles of a variety of round worms and flatworms. Niclosamide destroys the scolex and the adjoining proglottids of tapeworms, thereby loosening the worm’s holdfast. In these forms of therapy, the worms are unable to maintain their grip on the intestinal wall and are expelled along with the feces by the normal peristaltic action of the bowel. A drawback can be the severe abdominal cramps that often accompany treatment. Ivermectin is a broad-spectrum antiparasitic used in the treatment of roundworm infection and lice. It received a great deal of attention as a “treatment” for COVID-19 despite not showing any benefit to those taking it.
Antiviral Chemotherapeutic Agents
The chemotherapeutic treatment of viral infections presents unique challenges. Throughout our discussion of infections caused by bacteria, fungi, protozoa, and helminths, we’ve emphasized differences in structure and metabolism that guide drug choice. With viruses, we are dealing with an infectious agent that relies upon the host cell for the vast majority of its metabolic functions. Disrupting viral function may require that we disrupt the metabolism of the host cell to a much greater extent than is desirable. Put another way, selective toxicity with regard to viral infection can be difficult to achieve because a single metabolic system is responsible for the well-being of both virus and host. A few viral diseases, such as measles, mumps, and hepatitis, are routinely prevented by effective vaccinations. Un fortunately, vaccines are unavailable for many serious viral diseases, creating a real need for antiviral medications.
Over the past few years several antiviral drugs have been developed that target specific points in the infectious cycle of certain viruses. But due to marked differences among viruses, antiviral compounds tend to be limited in their spectrum.
Most antiviral drugs are designed to block a step in completion of the virus cycle. Major modes of action include
1. barring penetration of the virus into the host cell;
2. blocking replication, transcription, and/or translation of viral genetic material; and
3. preventing the normal maturation of viral particles.
Although antiviral drugs protect uninfected cells by keeping vi ruses from being synthesized and released, most are unable to eliminate extracellular viruses or those in a latent or persistent state within the host’s DNA. A summary covering the actions of several antiviral drugs appears in table 1.
Table1. Actions of Selected Antiviral Drugs *
Drugs for Treating Influenza
Zanamivir (Relenza) and oseltamivir (Tamiflu) are anti-influenza medications that block neuraminidase actions in both influenza A and influenza B viruses. Without the functions of neuraminidase, the virus cannot be budded off and released from the host cell, so cells cannot produce active viruses. Both types of drugs may be used prophylactically and must be given early in an infection to be most effective (table 1).
Baloxavir marboxil (Xofluza), blocks the initiation of viral RNA synthesis, pre venting replication of the influenza virus. Like Relenza and Tamiflu, Xofluva must be taken early in the course of infection to receive any benefit.
Antiherpes Drugs
Many antiviral agents mimic the structure of nucleotides (i.e., act as analogs) and compete for sites on replicating DNA. Once one of these nucleotide analogs is incorporated into the growing chain of DNA, replication of that strand stops, interrupting the viral life cycle.
Acyclovir (Zovirax) and the related compounds valacyclovir (Valtrex), famciclovir (Famvir), and penciclovir (Denavir) all work in this manner and (with small exceptions from drug to drug) can be used either orally or topically to treat common herpesvirus infections such as oral and genital herpes, chickenpox, and shingles. A related drug, ganciclovir (Cytovene), is used parenterally to treat cytomegalovirus infection in patients with compromised immune systems.
An interesting aspect of some of these antiviral agents (specifically valacyclovir and famciclovir) is that they are activated by an enzyme encoded by the virus itself, making the drug active only in virally infected cells. The enzyme thymidine kinase is used by the virus to process nucleosides before incorporating them into viral RNA or DNA. When the inactive drug enters a virally infected cell, the virus’s own thymidine kinase converts it to a working antiviral agent. In cells without viruses, the drug is never activated, and normal DNA replication is allowed to continue.
Antihepatitis C Drugs
Increased understanding of the viral life cycle has led to the virtual cure of hepatitis C, a disease affecting about 2.4 million people in the United States. A treatment regimen of two drugs, sofosbuvir and ledipavir, sold together under the brand name Harvoni, has led to a cure rate of 94% to 99% of persons infected with the most common form of the virus. Sofosbuvir is a nucleotide analog which targets the RNA polymerase responsible for replication of the hepatitis C genome, preventing synthesis of the RNA strand. Ledipasvir interferes with the function of a protein called NS5A (non- structural protein 5A) that is required for the RNA polymerase to function properly. Together, the two drugs have a synergistic effect. Similar drug combinations have shown comparable success. Zepatier is a combination of elbasvir (an NS5A inhibitor) and grazoprevir, a protease that is needed for viral replication, while Mavyret is a com bination of glecaprevir (a protease inhibitor) and pibrentasvir (an NS5A inhibitor). The primary drawback of these treatments is cost, which can approach $100,000 per treatment series (typically 8–16 weeks). Many medical experts feel the cure rate is worth the cost, however, as uncontrolled hepatitis C routinely leads to liver trans plant, at a far higher cost.
Drugs for Treating HIV Infection
The global epidemic of HIV-related disease has been a powerful stimulus for drug discovery. There is now a considerable array of drugs and drug combinations to manage HIV. All of the antiretrovial drugs target a specific part of the multiplication cycle of HIV. Currently, there are drugs that can inhibit or block every strategic step in the virus cycle (table 1).
One of the most important targets is the reverse transcriptase (RT) enzyme that HIV brings into the host cell. Recall from chapter 9 that HIV is a retrovirus with an RNA genome. Upon entering a host, the RNA is used as a template by reverse transcriptase to produce a DNA copy of this RNA. This activity offers two types of targets for anti-HIV drugs. One type of anti-RT drugs, nucleoside or nucleotide reverse transcriptase analogs (NRTIs), directly stops DNA synthesis through competitive inhibition. Zidovudine was the first NRTI and the first drug developed to treat HIV. It is an analog of thymine that becomes incorporated into the DNA strand of HIV but terminates synthesis because it does not offer the correct sites for binding additional nucleotides. Other examples are stavudine, lamivudine, didanosine, stavudine, and tenofovir.
The second type of anti-RT drugs are nonnucleoside reverse transcriptase inhibitors (NNRTIs) that attach to a site on the reverse transcriptase enzyme itself and alter its shape—a type of noncompetitive inhibition (table 2). NNRTIs accomplish a similar goal in preventing reverse transcription of the HIV RNA, but they bind to the enzyme itself and prevent its reactive site from synthesizing DNA. They are usually given together or in combination with NRTIs.
Table2. Overview of Anti-HIV Drugs, Effects, and Examples
Another enzyme essential to the virus’s release is HIV protease, which is involved in cutting the proteins that are an essential part of the virus structure (capsids, enzymes). The class of drugs called protease inhibitors has the effect of blocking this enzyme and causing the assembly of faulty viruses that are not infective.
Newer classes of anti-HIV drugs are two that block entry or fusion of the virus at the beginning of its invasion and one that prevents viral integration into the host genome. The drugs maraviroc and fostemsavir keep HIV out of cells by preventing the viruses from adhering to host cells, and without this step, they cannot invade. Enfuvirtide (Fuzeon) prevents infection when it stops the envelope of the virus from fusing with the host cell after it has attached. Another important enyzme targeted for HIV therapy is HIV integrase. This enzyme is essential for the final step in HIV DNA processing. Integrase inhibitors prevent this viral DNA from being incorporated or integrated into a host cell’s chromosome. Because this step must occur for full viral function, the cycle is terminated by this action.
The strategy for HIV treatment currently involves antiretroviral therapy (ART), which uses combinations of two, three, or four drugs in a single pill to reduce the development of drug resistance. Most treatments contain at least one NRTI and one NNRTI, while some add protease inhibitors and an integrase inhibitor. Examples include Cabenuva, Biktarvy, and Symtuza. For those who are uninfected with HIV but participate in activities that put them at higher risk of contracting the virus*, pre-exposure prophylaxis (PrEP)— the use of antiretroviral drugs by HIV-negative individuals to pre vent the acquisition of HIV—may be recommended. Two options exist: Truvada, which contains two NRTIs, and Biktarvy, which contains two NRTIs along with an integrase inhibitor. Table 2 summarizes HIV drug types, their modes of action, and examples.
Interferons A sensible alternative to artificial antiviral drugs has been the human-based substance interferon (IFN). Interferon is a glycoprotein produced primarily by fibroblasts and leukocytes in response to various immune stimuli. It has numerous biological activities, including antiviral and anticancer properties. Studies have shown that it is a versatile part of animal host defenses, having a major role in natural immunities.
The first investigations of interferon’s antiviral activity were limited by the extremely minute quantities that could be extracted from human blood. Several types of interferon are currently produced by the recombinant DNA technology techniques. Extensive clinical trials have tested interferon’s effectiveness in viral infections and cancer. Some of the known therapeutic benefits of interferon include
1. reducing the time of healing and some of the complications in certain infections (mainly of herpesviruses);
2. preventing or reducing some symptoms of cold and papilloma viruses (warts);
3. slowing the progress of certain cancers, including bone cancer and cervical cancer, and certain leukemias and lymphomas; and
4. treating a rare cancer called hairy-cell leukemia, hepatitis C (a viral liver infection), genital warts, and Kaposi’s sarcoma in AIDS patients.
Treatment of SARS-CoV-2
Over the past few years, more has been said about SARS-CoV-2, the virus that causes COVID-19, than any other virus, and so a few minutes spent on its prevention and treatment are certainly war ranted. To begin, a little context. Coronaviruses are widespread and well understood; most of them cause colds, and you’ve certainly been infected with several over the course of your lifetime. SARS CoV-2 is the third coronavirus to cause severe infection in humans. The previous two were SARS-CoV, which was responsible for 774 deaths in 2003, and MERS-CoV (Middle Eastern Respiratory Syn drome Coronavirus), which has led to roughly 900 deaths, mostly on the Arabian Peninsula, since 2012. All this is to say that this was not a new problem; strategies for the control and prevention of coronaviruses had been well-studied prior to the COVID-19 outbreak.
An important point is that severe COVID is the result of inflammation that damages the lungs, not strictly a result of the virus but rather the body’s reaction to infection. The first tried, and often most successful, therapies were aimed at reducing inflammation, not attacking the virus directly. Treatment with dexamethasone, a steroid that attenuates the body’s immune response (especially inflammation), significantly reduced death among the sickest patients. Other steroids—including budesonide, an anti-asthma medication—showed similar results, as did a monoclonal antibody treatment typically used for rheumatoid arthritis.
In terms of treatment directed toward the virus, the infusion of antibodies that bind to SARS-CoV-2 showed benefit, especially when given early in the course of the disease. These antibodies were isolated from the blood of people who had recovered from COVID, and because of this they are termed convalescent antibodies. Laboratory-created monoclonal antibodies, with a structure like those found in the bloodstream of recovering COVID patients, showed a similar effect. For severe infections, remdesivir—an adenosine analog that halts viral replication—showed benefits, shortening the average hospital stay from 15 to 10 days.
Two other antivirals used to fight SARS-CoV-2 performed so well that clinical testing was ended early, and the drugs submitted for emergency use authorization (this happens, rarely, when a drug shows such promise that the action of allowing the control group to remain untreated could be deemed unethical). Paxlovid, a combination of two protease inhibitors, blocks the activity of an enzyme that the coronavirus needs to replicate. When taken early in the course of infection—within five days of symptom onset—Paxlovid reduced hospitalization and death by 89%. A second drug, molnupiravir (marketed under the name Lagevrio) is a nucleoside analog originally developed as a broad-spectrum antiviral. Under similar conditions, Lagevrio reduced severe disease by about 30%. Both medications can be taken orally, simplifying administration. Because Paxlovid is far more effective, it is the treatment of choice in most cases, with Lagevrio serving as an alternative for those patients for whom Paxlovid is contraindicated (one of the protease inhibitors in Paxlovid displays several drug interactions, limiting its use).
The key to ending the COVID pandemic was not a medication at all, but the development of vaccines that both prevented severe illness and reduced the spread of the virus. Much more will be said about the body’s immune system, and the development of vaccines, in chapters 15 and 16.
