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A Brief Historical Overview of the Antimalarials Chloroquine And Iowa State University Capstones, Theses and Creative Components Dissertations Spring 2021 A brief historical overview of the antimalarials chloroquine and artemisinin: An investigation into their mechanisms of action and discussion on the predicament of antimalarial drug resistance Ekaterina Ellyce San Pedro Follow this and additional works at: https://lib.dr.iastate.edu/creativecomponents Part of the Chemicals and Drugs Commons Recommended Citation San Pedro, Ekaterina Ellyce, "A brief historical overview of the antimalarials chloroquine and artemisinin: An investigation into their mechanisms of action and discussion on the predicament of antimalarial drug resistance" (2021). Creative Components. 800. https://lib.dr.iastate.edu/creativecomponents/800 This Creative Component is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Creative Components by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. San Pedro 1 A Brief Historical Overview of the Antimalarials Chloroquine and Artemisinin: An Investigation into their Mechanisms of Action and Discussion on The Predicament of Antimalarial drug resistance By Ellyce San Pedro Abstract: Malaria is a problem that has affected humanity for millenia. As a result, two important antimalarial drugs, chloroquine and artemisinin, have been developed to combat Malaria. However, problems with antimalarial resistance have emerged. The following review discusses the history of Malaria and the synthesis of chloroquine and artemisinin. It discusses both drugs’ mechanisms of action and Plasmodium modes of resistance. It also further discusses the widespread predicament of antimalarial drug resistance, which is being combated by artemisinin-based combination therapy. Lastly, a case study is discussed concerning the reintroduction of chloroquine in areas where it has previously failed due to resistance. Introduction: Malaria or in Italian, “Mal ‘aria’” (Hempelmann & Krafts, 2013) has plagued humanity for millenia. From the ancient Egyptians in 1550 B.C. (Fagan, 2000) to the present day, historical records detail a deadly disease that results in symptoms such as shaking, fever, fatigue and death (CDC 2021). In the present day, Malaria has persisted, resulting in around 409,000 deaths in 2019 alone (CDC 2021). Prior to the modern day, Malaria’s origins were considered mysterious and miasmic in nature. But with the help of modern technology, great clinical advancements San Pedro 2 have been made in decreasing its potency. In particular, the antimalarial drugs chloroquine and artemisinin are today’s front-line defense against this dangerous disease. Parasite Life Cycle: Malaria is caused by a protozoan parasite. Malaria can be commonly contracted from four specific sporozoan species: P. malariae, P. falciparum, P. vivax and P. ovale (Fagan, 2000). The most common malarial infections are derived from the P. falciparum and P. vivax species (Fagan, 2000). The following parasite cycle can be used to generally describe the life cycles of the above listed parasites. The parasite life cycle requires a human host and a mosquito host (CDC 2021). The cycle begins when an infected female mosquito partakes in a human blood meal, which allows the entry of sporozoites into the skin (CDC 2021). The sporozoite then moves into the circulation (CDC 2021). Sporozoites are ambulatory parasites derived from a female anopheline mosquito that infects humans and targets human hepatocytes (WHO 2015). After sporozoite entry, a sporozoite infection of liver cells occurs. Sporozoites are obligate intracellular parasites that develop within the host cell during the vertebrate stage of the life cycle. The sporozoites then mature into schizonts (WHO 2015). Schizonts are mature malarial parasites that reside in the host’s liver cells where they undergo nuclear division (WHO 2015). Upon their maturation, the schizonts burst and release merozoites (CDC 2021). Merozoites are parasites that are released into the bloodstream when a liver cell bursts (WHO 2015). Upon formation, the merozoites proceed to invade erythrocytes. It is also important to note, that as the parasite grows within the erythrocyte, it must digest the host cell’s hemoglobin to acquire amino acids to support its metabolism and also to create more space in the host cell to San Pedro 3 grow. The sporogonic cycle or the sexual reproduction portion of the parasite life cycle occurs when the parasites multiply within the mosquito (CDC 2021). This occurs when parasite gametes are ingested by a mosquito in another blood meal. During the sporogonic cycle, the male microgametes fuse with female macrogametes to produce a zygote (CDC 2021). These zygotes will eventually mature into oocytes that will become sporozoites (CDC 2021). These sporozoites will be released from the mosquito’s salivary glands (CDC 2021). This continues the parasite’s life cycle as the mosquito continues taking blood meals. Past Explanations for Malaria: In the past, many explanations have been attributed to the cause of Malaria. Malaria was first attributed to miasma. Miasma was thought to be a dangerous cloud of particles that caused diseases (Hempelmann & Krafts, 2013). This led to the coinage of the Italian phrase “mal’aria”, indicating bad air (Hempelmann & Krafts, 2013). The idea of a malarial parasite was not introduced until microscopic staining techniques were able to detect the presence of the parasites in blood (Hempelmann & Krafts, 2013). Dr. Ronald Ross, a British army surgeon, was the first individual to prove that mosquitoes transmitted Malaria (Hempelmann & Krafts, 2013). In 1897, Ross obtained mosquitoes and gave them blood that had crescent-shaped cells (Murray, 1923). After feeding, Ross saw that there were pigmented crystals in the stomach wall (Murray 1923). Ross realized that mosquitoes do not normally produce the pigment known as hemozoin and he deduced that this pigment could be related to Malaria (Murray, 1923). Prior to this in 1880, Dr. Alphonse Laveragen discovered that Malaria was caused by a protozoan parasite (Nye, 2002). This discovery occurred when Dr. San Pedro 4 Laveragen, a military surgeon, visualized the malarial parasite through the use of blood smears (Nye, 2002). Past Treatments/Drugs Used to Treat Malaria: Antimalarial drugs have had a colorful history. Alternatives to quinine (the derivative for chloroquine), have included methylene blue dye, Prontosil and Atabrine (Lowe, 2020). Unfortunately, these drugs were not highly effective. They have also had the unfortunate side effect of turning patients into a whole spectrum of colors (Lowe, 2020). Methylene blue gave patients a blue tint. Prontosil turned patients into a permanent shade of red (Lowe, 2020). Atabrine gave individuals a yellow hue, while also causing depression, psychosis, seizures, and other problems (Lowe, 2020). In terms of today’s antimalarial treatments, the CDC states that common drugs that are used to treat Malaria include: atovaquone/Proguanil, and chloroquine (CDC 2021). However, chloroquine and artemisinin remain as the two frontline drugs that are most commonly used to combat the effects of Malaria. Chloroquine - A History: Chloroquine was discovered in 1934 by Johnann Hans Andersag (Lowe, 2020) from cinchona trees that are located in South America. Chloroquine is a weak base drug and it belongs to the family of 4-aminoquinolines (Coban, 2020). Quinolone was extracted in 1820 by researchers Pelletier and Caventou (Lowe, 2020). Quinine was synthesized in 1944 (Lowe, 2020). Unlike its predecessors, chloroquine possesses strong antimalarial activity and does not change the appearance of a patient's skin tones (Lowe, 2020). San Pedro 5 Chloroquine Mechanism of Action: Chloroquine's mechanism of action is still not fully understood. However, there are several suppositions that may explain how chloroquine functions in infected erythrocytes. An early theory for chloroquine’s mechanism of action focused on chloroquine’s ability to bind DNA and RNA (Coban, 2020). It was previously thought that chloroquine would bind to the host cell’s DNA and RNA through hydrogen bonds and electrostatic forces (Coban, 2020). However, DNA-chloroquine interactions required an excessively high concentration of chloroquine to occur (Coban, 2020). This amount was much higher than needed to eliminate parasites, therefore making it unlikely that this supposition was true (Coban, 2020). The second and more substantial mechanism of action relies on chloroquine’s interactions with free-heme in the infected erythrocyte. Chloroquine weakens the malarial parasite by reducing its ability to synthesize hemozoin, a substance that is significant to Plasmodium survival (Pilat et al, 2020). In the absence of antimalarial drugs, the malarial parasite performs hemoglobin degradation using proteases such as plasmepsins and falcipains (Coban, 2020). Plasmepsins and falcipains are a part of Plasmodium-specific families of aspartic proteases and cysteine proteases. These proteases catabolize hemoglobin to release peptides and nutrients that the parasite requires to survive (Wicht et al, 2020). However, it has also been shown that many of these amino acids are returned to the serum. Thus, hemoglobin degradation is also surmised to create space in the infected erythrocyte for parasite growth (Krugliak et al, 2002). San Pedro
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