TY - JOUR
T1 - Probing for Antiparasitic Drugs
AU - Golenser, Jacob
AU - Hunt, Nicholas H.
AU - Sarel, Shalom
PY - 2006/2
Y1 - 2006/2
N2 - Every person on earth is infected by at least several parasites. The most dangerous parasites are transmitted by vectors and cause the death of millions annually. In order to reduce mortality resulting from such infections there is a need to interrupt the life cycle of the parasites. A parasitic disease will not be eradicated unless efforts to contain it below a "critical mass" succeed. The critical mass may be defined as a combination of a minimum number of infected human, infected reservoir animals (when relevant, e.g. leishmaniasis), and a minimum amount of vectors (e.g. Simulium in river blindness). A failure to control the vectors and insufficient treatment of human patients originates from the increasing resistance of the vectors to insecticides and from parasite drug resistance. In addition, economic considerations are highly responsible for the prevalence of the diseases. In this issue our aim is to consider novel and recent approaches to chemotherapy of vector-born parasitic diseases. Recent advances regarding the biology, physiology and biochemistry of the parasites have led to the recognition of new targets for chemotherapy. These targets must be specific in order to increase the therapeutic value of the drug. Lead optimization may help in designing new drugs such as enzyme inhibitors. For example, cysteine proteases of various parasites could be an important target; in malaria parasites they are involved in hemoglobin degradation and in Leishmania parasites in digestion within lysosomes/endosomes. A second approach to drug discovery is based on the screening of traditional drugs. Some of these compounds were used long before the understanding of their mechanism of action and some are still in use despite their unknown mechanism (e.g. quinine). A third approach aims at improvement of existing drugs by derivatization, which enables better transport to the target cell/organ (e.g. diamidine derivatives against sleeping sickness) or slow release in order to allow for sufficient stable amounts of the drug. Despite the continuous, extensive studies being carried out, the amount of newly approved effective anti-parasitic drugs in the last 5 years, is frustrating and can be counted on the fingers of one hand. A main reason for the limited success of developing new drugs is the lack of understanding of mechanisms of drug action which are additional to the direct anti-parasitic effects. While it is relatively easy to examine drug effects on in vitro cultures of the parasite, the actual activity, efficacy and safety of drugs depend on various factors. These include the direct anti-parasitic effect, and the effect on immune and physiological functions. These considerations could be demonstrated by artemisinin and its derivatives. Artemisinin is a prodrug which is transformed to the active derivative dihydroartemisinin (DHA). It is a common dogma that it is active because it contains a peroxide bridge which interacts with iron to form a reactive free radical. Despite its accumulation in the parasitized erythrocyte its high anti-malarial therapeutic index can not be solely attributed to its radical activity. DHA in vitro kills bacteria, various protozoa (e.g. Leishmania) and animal cells at μM concentrations. However, the ID50 for malaria parasites is lower than 1 nM. This low ID50 has been attributed to DHA's activity against the plasmodial SERCA (Ca-ATPase). There are additional effects which are not anti-parasitic but affect the fate of the malaria infected patient: DHA reduces vascular endothelial growth factor (VEGF) which consequently may affect the pathogenesis of in vivo infection. Moreover, treatment with high concentrations of DHA may suppress both humoral and cellular immune responses. Low concentrations may stimulate T-lymphocyte cell mediated responses. The therapeutic index of a drug would be increased if large amounts could be targeted to the affected host organ and parasite molecule. The outmoded former drug chloroquine was a most valuable drug because it was accumulated in the parasitized erythrocyte and has a specific target which is related to hemoglobin degradation and hemozoin formation. Chloroquine is not in use any more due to plasmodial drug resistance. It took more than 20 years until chloroquine resistance spread throughout all endemic areas. However, sometimes it is possible to predict the probability of induction of drug resistance by exposing the parasites to increasing quantities of the drug and by using molecular markers. J. Clos and K. Choudhury use functional cloning as a means to identify Leishmania genes involved in drug resistance. Resistance to established anti-leishmanial drugs is a mounting problem in high-endemicity regions and in the context of HIV-Leishmania coinfections. The molecular basis for clinical........
AB - Every person on earth is infected by at least several parasites. The most dangerous parasites are transmitted by vectors and cause the death of millions annually. In order to reduce mortality resulting from such infections there is a need to interrupt the life cycle of the parasites. A parasitic disease will not be eradicated unless efforts to contain it below a "critical mass" succeed. The critical mass may be defined as a combination of a minimum number of infected human, infected reservoir animals (when relevant, e.g. leishmaniasis), and a minimum amount of vectors (e.g. Simulium in river blindness). A failure to control the vectors and insufficient treatment of human patients originates from the increasing resistance of the vectors to insecticides and from parasite drug resistance. In addition, economic considerations are highly responsible for the prevalence of the diseases. In this issue our aim is to consider novel and recent approaches to chemotherapy of vector-born parasitic diseases. Recent advances regarding the biology, physiology and biochemistry of the parasites have led to the recognition of new targets for chemotherapy. These targets must be specific in order to increase the therapeutic value of the drug. Lead optimization may help in designing new drugs such as enzyme inhibitors. For example, cysteine proteases of various parasites could be an important target; in malaria parasites they are involved in hemoglobin degradation and in Leishmania parasites in digestion within lysosomes/endosomes. A second approach to drug discovery is based on the screening of traditional drugs. Some of these compounds were used long before the understanding of their mechanism of action and some are still in use despite their unknown mechanism (e.g. quinine). A third approach aims at improvement of existing drugs by derivatization, which enables better transport to the target cell/organ (e.g. diamidine derivatives against sleeping sickness) or slow release in order to allow for sufficient stable amounts of the drug. Despite the continuous, extensive studies being carried out, the amount of newly approved effective anti-parasitic drugs in the last 5 years, is frustrating and can be counted on the fingers of one hand. A main reason for the limited success of developing new drugs is the lack of understanding of mechanisms of drug action which are additional to the direct anti-parasitic effects. While it is relatively easy to examine drug effects on in vitro cultures of the parasite, the actual activity, efficacy and safety of drugs depend on various factors. These include the direct anti-parasitic effect, and the effect on immune and physiological functions. These considerations could be demonstrated by artemisinin and its derivatives. Artemisinin is a prodrug which is transformed to the active derivative dihydroartemisinin (DHA). It is a common dogma that it is active because it contains a peroxide bridge which interacts with iron to form a reactive free radical. Despite its accumulation in the parasitized erythrocyte its high anti-malarial therapeutic index can not be solely attributed to its radical activity. DHA in vitro kills bacteria, various protozoa (e.g. Leishmania) and animal cells at μM concentrations. However, the ID50 for malaria parasites is lower than 1 nM. This low ID50 has been attributed to DHA's activity against the plasmodial SERCA (Ca-ATPase). There are additional effects which are not anti-parasitic but affect the fate of the malaria infected patient: DHA reduces vascular endothelial growth factor (VEGF) which consequently may affect the pathogenesis of in vivo infection. Moreover, treatment with high concentrations of DHA may suppress both humoral and cellular immune responses. Low concentrations may stimulate T-lymphocyte cell mediated responses. The therapeutic index of a drug would be increased if large amounts could be targeted to the affected host organ and parasite molecule. The outmoded former drug chloroquine was a most valuable drug because it was accumulated in the parasitized erythrocyte and has a specific target which is related to hemoglobin degradation and hemozoin formation. Chloroquine is not in use any more due to plasmodial drug resistance. It took more than 20 years until chloroquine resistance spread throughout all endemic areas. However, sometimes it is possible to predict the probability of induction of drug resistance by exposing the parasites to increasing quantities of the drug and by using molecular markers. J. Clos and K. Choudhury use functional cloning as a means to identify Leishmania genes involved in drug resistance. Resistance to established anti-leishmanial drugs is a mounting problem in high-endemicity regions and in the context of HIV-Leishmania coinfections. The molecular basis for clinical........
UR - http://www.scopus.com/inward/record.url?scp=33646021902&partnerID=8YFLogxK
U2 - 10.2174/138955706775475920
DO - 10.2174/138955706775475920
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C2 - 16472180
AN - SCOPUS:33646021902
SN - 1389-5575
VL - 6
SP - 121
EP - 122
JO - Mini-Reviews in Medicinal Chemistry
JF - Mini-Reviews in Medicinal Chemistry
IS - 2
ER -