List of filarial worms with their habitats and intermediate host infecting humans.
Abstract
Filariasis is one of the most debilitating tropical neglected diseases with high morbidity rate and less rate of mortality with various clinical symptoms. According to the World Health Organization (WHO) reports, about 120 million people from 81 countries are infected at present, and an estimated 1.34 billion people live in areas endemic to filariasis and are at risk of infection. Currently available drugs are only effective against the larval stage of the worms with side effects, and their repetitive use gives rise to drug resistance. Till date, no effective vaccine is available for the treatment of filariasis; to fulfill this need, new drug development becomes the priority for the researchers. This chapter reviews different synthetic and natural origin drugs, drug targets, and use of bioinformatics to discover new antifilarial agents which can control this debilitating disease, including the types of filariasis, their prevalence, and eradication programs which are discussed.
Keywords
- filariasis
- drug targets
- antifilarials
- bioinformatics
1. Introduction
A variety of parasitic diseases which are associated with morbidity and mortality have received less attention worldwide. Among these, filariasis is one of the most debilitating neglected tropical diseases. Filariasis is a vector-borne disease transmitted by arthropod vector which is endemic in the tropics and subtropics that results in social stigma. It is a group of human and animal infectious diseases caused by nematode parasites generally called “filariae” that include several hundred species of worms that are slender and elongated and are parasitic in tissues of various vertebrate hosts. This parasite known to cause human infections belongs mainly to the genera
Filarial worm | Habitat | Intermediate host | Disease |
---|---|---|---|
Lymphatics | Mosquito sp. | Elephantiasis | |
Lymphatics | Mosquito sp. | Malayan filariasis | |
Lymphatics | Mosquito sp. | Timor fever | |
Connective tissue | Loaiasis | ||
Serous membranes | Ozzard’s filaria | ||
Skin | Onchocerciasis |
According to recent surveys, about 120 million people in 81 countries of the world are infected from this disease, and 1.34 billion people who live in endemic areas are at high risk of this life-threatening infection [1]. To eradicate filariasis globally, research plans are needed to design effective drugs and drug targets, new vector control strategies, and diagnostic techniques. At the same time, the treatment of filariasis also requires disease-specific clinical care and patient education with counseling to eradicate this disease. Moreover, statistical analysis along with bioinformatics tools of the mass drug administration (MDA) surveillance reports should be carried out which could provide new opportunities to get an insight into the proteins or genome which may contribute to its inhibition process.
In current surveillance report, five World Health Organization (WHO) regions are endemic with lymphatic filariasis (LF). Worldwide, 1.39 billion people require preventive chemotherapy. In Southeast Asia region, 877 million people of 9 countries and 432 million people of 39 countries in the Africa region are brutally affected from this disease and require proper treatment. From the Western Pacific Region which includes the Mekong Plus region and the Pacific region, nearly 40 million people are at a risk of lymphatic filariasis. Cambodia, China, Cook Islands, Niue, the Marshall Islands, Palau, the Republic of Korea, Tonga, Vanuatu, Viet Nam, and Wallis and Futuna are the countries of this region that successfully eradicated this disease, whereas American Samoa, Brunei Darussalam, Fiji, French Polynesia, Kiribati, Lao People’s Democratic Republic, Malaysia, Federated States of Micronesia, New Caledonia, Papua New Guinea, Philippines, Samoa and Tuvalu are the 13 countries where lymphatic filariasis remains endemic [1, 2].
2. History of filariasis
In India first, ancient documented evidence of filariasis was reported in
3. Filariasis: an overview
Among all the filariasis, lymphatic filariasis is the most debilitating which causes disability in humans.
Data collected from the survey depicted the picture of depressive illness of an individual caused by LF and estimated 5.09 million disability-adjusted life years (DALYs) [3, 4, 5]. In infants microfilaremia starts at the age of 5 after acquiring infection, but the actual signs of filariasis (including hydroceles) appear during puberty. Previous survey reports indicated that once the individual acquired infection chances of cure becomes very low [6].
Filarial worms inhabiting the lymphatic system live up to 8 years and release millions of microfilariae into the bloodstream. The WHO started the Global Alliance to Eliminate Lymphatic Filariasis (GPELF) in 2000 with the goal of eradicating this disease by 2020 through the use of MDA [7]. In the history of public health, GPELF is the most successfully expanding global health program. Fifty-three out of the 81 endemic countries have started mass drug administration to halt the transmission of filariasis. Two strategies have been developed to achieve the target of eliminating filariasis. According to the first strategy, single annual doses of diethylcarbamazine or ivermectin plus albendazole will be provided to the entire endemic area to prevent the disease. The second strategy is to reduce disability rate by providing knowledge about how to maintain hygiene and skin care, to those with lymphedema and performing surgery in patients with hydrocele. The investment for chemotherapy to control this disease is approximately US$ 105–208 million per year during 2015–2020. The WHO determined two objectives, which include “70% of endemic countries demanding MDA will have to enter post-intervention surveillance by 2016” and “all other endemic countries have to complete the post-intervention surveillance by 2020” [8, 9]. The abovementioned antifilarial drugs are only effective against the microfilariae and have no effect on the adult worms which therefore provide a partial treatment to the infected individuals. Repetitive use of these drugs resulted in drug resistance. Till date no vaccines are developed, and treatment depends only on the antifilarial. Researchers are developing various new antifilarials and combination therapies to overcome this disease [10].
4. General life cycle of filarial worm
Man is the definitive host of filarial worm, in whose lymphatic system, the adult worms reside. Adult females discharge the live embryo called microfilariae (290 μ). Microfilariae flow in the peripheral blood and can survive for a considerable time without undergoing metamorphosis until they are taken up by the intermediate host, i.e., the culicine mosquitoes during their blood meal. After reaching in the mosquitoes, microfilariae undergo development and become infective-stage larvae as described in Figure 1.
5. Diagnosis of lymphatic filariasis
LF is primarily diagnosed using the immunochromatographic card test kit via antigen detection methods (which also detects latent infections). The traditional diagnosis of LF is performed by microscopy to detect circulating microfilariae. Molecular xenomonitoring of parasites in mosquitoes, serological testing, ultrasonography, PCR tests, lymphoscintigraphy, detection of exposure to transmission in children via antibody detection, and the recently introduced filariasis test strip (FTS) are some of the other diagnostic approaches that are currently used.
6. Biological point for designing new drug
A clear knowledge of parasite physiology is very important to identify drug targets for understanding the mode of action of antifilarial drug. Sometimes compounds are also tested, without prior knowledge of the target. Compounds which are effective against the whole parasite are defined as hits, while compounds that are found to be active in vivo are considered as leads. Lead compounds require standardization for increasing their efficacy. Once a compound is optimized, it can be tested clinically in patients and defined as a “drug candidate.” Based on the physiological processes and symptoms, a drug should be formulated and designed to combat the disease. To overcome filariasis a number of drug targets should be covered for developing new antifilarial, viz., macrofilaricidal and microfilaricidal drugs, drugs preventing exsheathment in microfilariae and drugs that can cause hindrance in the movement of microfilariae. Different biochemical pathways are summarized in Table 2 which are used in designing new drugs. On the other hand, vaccine development and mosquito repellent practices such as the use of insecticide nets, body lotions, insecticides spray, coils, etc. along with good knowledge of sanitization can prevent vector development which together helps in combating filarial worm infection in a community. The pathology associated with lymphatic filariasis like elephantiasis, hydrocoele, and lymphedema is due to the hyporesponsiveness of D4+ T cells of the host immune system [11, 12, 13]. Therefore, immunological studies are also playing an important role in the field of drug development. Drugs are also designed to combat symptoms associated with filariasis, viz., drugs used for the treatment of lymphatic filariasis (drugs effective against adenolymphadenitis, funiculitis, epididymo-orchitis, lymphedema, hydrocele, chyluria, chylocele, lymph scrotum) and drugs used in the treatment of other manifestations like asymptomatic microfilaremia, occult filariasis, onchocerciasis, and loaiasis.
Contribute to the nucleotide pool of nematodes | Tetracycline was resulted in the depletion of these |
|
Bacteria-specific filamenting temperature-sensitive protein (important in bacterial cytokinesis) that was expressed in all developmental stages of |
||
Myristoyltransferase (NMT) | The addition of myristic acid, a 14-carbon unsaturated fatty acid, to the N-terminus of glycine in a subset of proteins via myristoyl-CoA:protein N-myristoyltransferase (NMT) promotes their binding to cell membrane | A known NMT enzyme inhibitor in tripanosomatids, DDD85646, and its analog DDD100870, were tested against |
Proteins and amino acids | ||
---|---|---|
Free amino acids are required for intracellular osmoregulation and protein synthesis | ||
S-adenosylmethionine methyltransferase, methionine adenosyltransferase, and S-adenosylhomocysteine hydrolase | Are required for the conversion of methionine to homocysteine in the methionine | |
Enzyme prolyl-4-hydroxylase has been reported to | Play a vital role in the biosynthesis of this collagen | |
Transaminoglutamase | Play a significant role in the growth, development, and maturation of the nematode | A pseudosubstrate, monodansylcadaverine (MDC), and active site inhibitors cystamine or iodoacetamide were found to inhibit L3-stage parasite mobility in a dose-dependent manner that was associated with irreversible biochemical lesions, resulting in the death of the parasite |
Retinoic acid-binding proteins (RABPs) | Parasitic nematodes require lipophilic retinol for various biological processes, such as embryogenesis, differentiation, and growth For inter- as well as intracellular movement |
Ivermectin(II) was found to compete efficiently with retinol for the retinol-binding sites on RBP of the parasite but not for the host RBP sites |
Norepinephrine (NE), histamine, 5-hydroxytryptamine (5-HT), and dopamine | Biogenic amines play a role in neuromuscular activity and behavioral coordination in nematodes | |
Monoamine oxidase (i.e., MAO), acetylcholinesterase, and dopamine-b-hydroxylase | DEC, levamisole, and centperazine were found to inactivate these enzymes | |
Dopamine-b-hydroxylase | ||
Octopamine | ||
Putrescine, spermine, and spermidine | Are required for growth, differentiation, and macromolecular synthesis in all living organisms as constituents of the polyamine salvage pathway | |
S-adenosylmethionine decarboxylase (SAMDC) | Which is required for polyamine biosynthesis | Berenil and aromatic methylglyoxal bis(guanylhydrazone) analogs are inhibitors of an important regulatory enzyme |
Fructose 1,6-diphosphate aldolase | Its immunogenic component in filarial worms is distinguishable from that of mammals, thus identifying it as possible vaccine target238 | |
Phosphoenolpyruvate carboxykinase | Inhibited by DEC | |
Fumarate reductase | Inhibited by DEC and benzimidazoles | |
Succinate dehydrogenase | Inhibited by DEC | |
Phosphofructokinase | Blocked by antimonial stibophen in |
|
Glucose uptake | Altered by DEC, amoscanate, and arsenicals | |
Utilization of glucose | Decreased by levamisole |
Lipid metabolism | ||
---|---|---|
Quinones | Play a role in filarial electron transport | |
Geranyl geraniol | Unknown role | The biosynthesis of genanyl geraniol and dolichols was inhibited by mevinolin |
Juvenile hormones | Regulators of larval development | |
Dolichols | Required for glycoprotein synthesis | |
Isopentyl pyrophosphate | IPP constituent of filarial tRNA | |
HMG-CoA reductase is a rate limiting enzyme | Involved in the isoprenoid pathway of filaria | Inhibited by mevinolin |
Enzymes, such as reductases, transferases, synthases, dehydrogenases, hydrolases, mutases, ligases, and deaminases | Are involved in the interconversation of folate analogs observed in the synthesis of different tetrahydrofolate cofactors by macrofilariae. Specifically, dihydrofolate reductase activity, which is commonly observed in macrofilariae, was found to be absent in the microfilariae of |
DEC and suramin were found to inhibit some enzymes involved in folate metabolism |
10-Formyl FH4 dehydrogenase enzyme | Which was found to play a vital role in the regulation of the endogenous FH4 cofactor concentrations, was more active in |
|
Glutamate-cysteine ligase (rate-g-glutamyl transpeptidase) | Glutathione has been proposed to constitute the antioxidant system (g-glutamyl cycle) that extends the survival of filarial parasites in mammalian hosts, thereby protecting them from host-mediated membrane lipid peroxidation | Arsenicals depletes filarial glutathione (262–264) Phytocompounds such as plumbagin, curcumin, and a phenoxyacetic acid derivative were found to inhibit filarial GST In a report of a homology modeling approach via in silico analysis of the filarial GST of |
Glutathione-transferases (GSTs) | The major detoxifying systems in filarial parasites and can detoxify cytotoxic products of lipid peroxidation via the conjugation of glutathione (GSH) to various endogenous xenobiotic electrophiles |
7. Currently used antifilarial drugs
7.1 Diethylcarbamazine (DEC)
Diethylcarbamazine (DEC), a piperazine derivative, is the most common and widely used drug over many decades. The antifilarial activity of DEC was first tested against
7.2 Ivermectin (IVM)
It is a broad-spectrum anthelmintic and an effective macrofilaricidal drug introduced in 1981 also known as Mectizan [2], which was the first commercially available macrocyclic lactone. Chemically, it is a 22,23-dihydro semisynthetic derivative of avermectin B1, which is a fermentation product of actinomycetes
7.3 Suramin
Suramin [35] initially was a drug used to cure trypanosomiasis and onchocerciasis. Chemically it is an 8,80-(carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino])bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt. Presently it is the only macrofilaricidal drug that is effective against
7.4 Albendazole
This anthelmintic drug is [24] a benzimidazole derivative. Recently this has been used in a clinical trial to check out its efficacy as antifilarial drug [36]. Its efficacy was increased when administered in combination with either DEC [8] or IVM [2].
7.5 Levamisole
This is an ascaricidal drug with no side effects at the recommended doses. It has also been found as a microfilaricidal drug against the microfilariae of
Unfortunately, most of the chemical antifilarials are characterized by adverse side effects. The list of currently used antifilarials with their side effects is summarized in Table 3. Hence, researches on exploring new therapeutic drugs, especially less hazardous drugs of natural origin, are highly recommended. The application of biomedicines to treat disease is among the oldest forms of therapy. These biomedicines including plant extracts and their secondary metabolites were believed to exert their bioefficacy through immunomodulatory elicitation of Th1/Th2 response, either by single (Th1, Th2) or mixed adjuvant activity. Therefore, in the context of filariasis, synthetic and naturally originated antifilarials are summarized in Tables 4 and 5.
Antifilarial agent | Recommended dose | Route of administration | Mechanism of action | Filarial worm | Side effects |
---|---|---|---|---|---|
Diethyl carbamazine (piperazine derivative) | 6 mg/kg for 12 days (individual treatment) 6 mg/kg in 24 hours (weekly/monthly/single annual dose in mass treatment) for treating |
Oral | Alterations in arachidonic acid metabolism of host endothelial cells and microfilariae, resulting in blood vessel constriction and host granulocyte and platelet aggregation; apoptosis and org nelle damage | Encephalitis and retinal hemorrhage. Increasing dose include systemic reaction: nausea, GIT upset, malaise, body aches, and anorexia. Localized reactions: abscess formation, lymphadenitis, and transient lymphedema | |
3–6 mg/kg for 6–12 days (individual treatment) 3–6 mg/kg in 24 hours (6 times at weekly or monthly in mass treatment) for treating |
|||||
8 mg/kg for 14 days For the treatment of occult filariasis |
Occult filariasis | ||||
Table salt + Diethylcarbamazine | 0.1% for 6 months treatment of LF | ||||
0.3% for 3–4 months |
|||||
Ivermectin (macrocyclic lactone) | 400 mg/kg single dose treatment 4800 mg/kg for 6 months treatment |
Oral | Targets glutamate gated Cl- and K+ ion channels in nematodes, results in hyperpolarization that causes paralysis of the body wall muscle and pharynx. The drug also affects ligand-gated chloride ion channels gated by GABA. It competes with retinol for the retinol-binding site on retinol-binding proteins (RBPs) in the parasite only | Bancroftian and brugian filariasis | Same as DEC, and special care must be considered, such as avoiding its use in cases of pregnancy and in children younger than 5 years old |
Suramin | 66.7 mg/kg in 6 incremental weekly doses (3.3, 6.7, 10.0, 13.3, 16.7, 16.7 mg/kg for the first and sixth weeks, respectively) | Intravenous (10% solution in water) | It adversely affects enzymes associated with glucose catabolism and destabilizes DNA and protein kinase enzymes in filarial worms | Fatal collapse, albuminuria, ulceration, and persistent high fever; polyuria, tiredness, tenderness, anorexia, and increased thirst; among others are some of the milder side effects | |
Levimazol | An initial dose of 100 mg followed by the same dose twice daily for 10 days was found to be as effective as the total oral dosage of DEC at 126 mg per kg body weight | Oral | Acts as nicotinic receptor agonist that causes prolonged activation of the excitatory nicotinic acetylcholine (nACh) receptors on the body wall muscle of parasites, leading to spastic muscle paralysis in the worm | No side effects at recommended doses | |
Albendazole (benzimidazole) Albendazole+ DEC |
Albendazole (400 mg) + diethylcarbamazine (DEC) (6 mg/kg) | Oral | Block tubulin polymerization, thereby inhibiting microtubule formation. It also inhibits parasite intestinal cells, preventing glucose uptake leading to the death of the parasite | Macrofilaricidal | Embryotoxicity and teratogenicity |
Albendazole+ ivermectin | Albendazole (400 mg) + ivermectin (150–200 mg/kg) |
Antifilarial agent | Action | Parasite | Dose | Reference |
---|---|---|---|---|
Trisubstituted pyrimidine derivatives (the amino group and 4-aminophenyl group at the second position plays an important role in exerting antifilarial activity) | ATP-dependent DNA topoisomerase II inhibitory activity | 10–40 mg/ml | [38, 39] | |
2-Sulfanyl-6-methyl-1,4-dihydropyrimidines | 25 and 50 μM 100 mg/kg |
|||
Indole derivatives B-carboline | 30 mg/kg for 5 days 50 mg/kg for 5 days |
[40, 41, 42, 43] | ||
b-Carbolines (substituted 9Hpyrido[3,4-b]indoles) | 50 mg/kg for 5 days | |||
Quinoline and related compounds 7-chloro-4-(substituted amino)quinolines | [44, 45, 46, 47] | |||
3-Nitro-4-quinolones via ipso-nitration | Thymidylate kinase inhibitory activity | IC50 2.9 mM | ||
Quinolones compound 7-chloro-4-(substituted amino)quinolines | Evaluation against DNA topoisomerase II enzyme, compound | Screened in vivo against |
200 mg/kg for 5 days | |
3-Nitro-4-quinolones | IC50 2.9 mM | |||
Glycoside cinnamoyl glycosides | MIC (3.40 nM), IC50 (6.90 nM) and LC50 (25 nM) values, CC50 value of approximately 103 nM | [48] | ||
Cinnamoyl glycosides | Chromatin condensation and DNA fragmentation; this compound also damaged the cuticular sheath of the microfilariae | MIC and IC50 values were 4.4 nM/ml and 8.96 nM/ml, respectively | ||
Dioxocine 3,6-epoxy dioxocines | IC50 values (0.4 mg/ml and 1.8 mg/ml, with selectivity indices (SI) of 100 and 22.2 with respect to macrofilariae and microfilariae, respectively | [49] | ||
Compound | Found to be potent in terms of both in vitro (IC50 1.6 mg/ml and 3.5 mg/ml for macrofilariae and microfilariae, respectively) and in vivo antifilarial activity, 200 mg/kg | |||
Alcohols cyclohexanol, 2- substituted propanol Cyclooctanol derivatives |
100% macrofilaricidal activity (at a dose of 200 mg/kg for 5 days) 81% sterilization of female worms (at a dose of 100 mg/kg for 5 days) against |
[50] | ||
Triazine | DHFR (dihydrofolate reductase) inhibitors, good inhibitory activity (approximately 74%) against PARP (polyadenosine diphosphate ribose polymerase)enzyme | Almost 100% loss of motility of filarial worms at 20 mg/ml showed better activity (IC50 10.90 mM) when compared with standard antifolate (positive control) compounds, i.e., trimethoprim (IC50 12.92 mM) and pyrimethamine (IC50 20.10 mM | [51, 52] | |
Benzopyran (coumarin) | When administered orally at a dose of 300 mg/kg for 5 days showed 53.6% macrofilaricidal and 46% microfilaricidal activity At a dose of 100 mg/ kg for 5 days, showed 75% adulticidal and 50% microfilaricidal activity |
[53, 54, 55] | ||
Naphthalene derivative 1,4-naphthoquinones | 1,3-Dimethyl substitution on the butylamino side chain favors an increased lipophilicity with potentially improved binding to the active site, which results in elevated macrofilaricidal activity (133) | ED50 value of 2.6 mM after a 24 h incubation and 0.91 mM after a 48 h incubation | [56] | |
Thiazolidine heterocyclic thiazolidine compounds compound (31) and compound (32) | IC50 values of 5.2 mM and 1.78 mM LD50 values of 349 mM and 17.59 mM, respectively |
[14] | ||
Butylated hydroxy anisole (BHA) | Oxidative stress-induced apoptosis was found to be its major killing mechanism (135) | At 100 mM was found to be a potent adulticide | [15] | |
Piperazine benzoyl piperazine derivatives (two compounds, viz., compound (34) and compound (35) containing a 4-chloro (para) substituent and 3-methyl (meta) substituent on the aromatic ring) | Worms were immotile following treatment with these two compounds at a concentration of 8 mg ml 1 | [16, 17, 57] | ||
Pyrrolidine chalcone derivative (36) containing the pyrrolidine-methoxy group | Showed a significant suppression of glutathione-S-transferase (GST) activity in the macrofilariae of female |
100% inhibition | ||
Diaminoalkane N1,Nn-xylofuranosylated diaminoalkanes | At 50 mg kg 1 provided approximately 38.7% recovery of macrofilariae and 63.80% sterilization of female parasites The same compound also showed 33.5% adulticidal action along with 50% sterilization of female worms |
[58] | ||
Secondary amines | At a dose of 200 mg/kg for 5 days exhibited 100% macrofilaricidal activity, whereas compound elicited a microfilaricidal response of approximately 93% | [59] | ||
Glycyrrhetinic acid derivatives and the benzylamide analog | Killing microfilariae and macrofilariae at 50 and 25 mM, respectively The IC50 values were found to be 2.2 mM against microfilariae and 8.8 mM against macrofilariae of the worm |
[60] | ||
At a dose of 100 mg/kg for 5 days exhibited 40% adulticidal activity | ||||
Nitazoxanide and tizoxanide | The researchers further reported that both compounds reduced microfilarial production and impaired embryogenesis in female worms. They also suggested that mitochondria in the worms may be a possible target of NTZ (41) and TZ (42) because in addition to damaged worm tissues, they found alterations in the mitochondria | Macrofilariae were found completely immotile after 6 days when cultured with these two compounds at concentrations of 20 mg/ml On day 8 of culture at concentrations of 2.5 mg/ml, both drugs also caused a 50% decrease in worm viability Microfilarial motility was also hampered by these compounds at concentrations exceeding 5 mg/ml, and the worms were completely immotile following treatment with 20 mg/ml (after 48 h) |
[61] | |
Nitazoxanide Nitazoxanide + silver nanoparticles |
Inhibit TCA cycle enzymes | 100% mortality of microfilariae at 100 μg/ml 100% mortality of microfilariae at 30 μg/ml |
[62, 63] | |
Anthraquinone 3-methylcatechol with a substitution of acylium ions | Marked effects on intrauterine embryos of parasite | At 5 ppm (18–19 mM) showed 100% mortality within 1, 5, and 3 days against microfilariae and adult male and female worms | [64] | |
Sulfonamide sulfonamide chalcones | IC50 value was found to be 4.4 mM, LD50 value of 188 mMt 500 mM concentration after 48 h of incubation | [65] | ||
Benzothiazole novel chalcone–benzothiazole hybrids | It showed higher binding interactions at the active site of BmTMK ( |
IC50 values of 2.12 mM and 1.63 mM, respectively, for adult worms as well as microfilariae MIC value of 5 mM for both the forms IC50 value was 95.3 mM |
[66] | |
Thiazole chalcone–thiazole derivatives | At a dose of 100 mg/kg for 5 days showed 100% embryostatic activity Exerted approximately 49% macrofilaricidal activity and |
[67] | ||
Benzimidazole derivatives HOE 33258 mebendazole, Flubendazole 2,2′-Dicarbomethoxyamino-5,5′-dibenzimidazolyl ketone |
At 5 × 2.5 mg/kg and 1 × 25 mg/kg in jirds and 1 × 100 mg/kg in cats when administered by subcutaneous injection A dose of 3 mg/kg (i.p.) and 50 mg/kg (oral) × 5 days of Comp. 82/437 At a dose of 150 and 200 mg/kg for 5 days |
Evaluated in jirds ( |
Macrofilaricidal. It also killed developing larvae in jirds. It was not microfilaricidal Eliminated almost 100% of adult worms and microfilariae It killed 100% of the macrofilariae and 97% of the microfilariae |
[68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] |
Silver | Nanosilver | LD50 concentration (by trypan blue exclusion) of 101.2 mM and an IC50 value of 50.6 mM (complete microfilariae population found immotile). At 4.6 mM only, nanosilver caused a 50% decrease in the motility of the parasite | [80] |
Plant | Extract | Target | Antifilarial efficiency | Author |
---|---|---|---|---|
Three new tirandamycins | Inhibit the asparaginyl-tRNA-synthetase (BmAsnRS) enzyme at an IC50 value of 30 mM | [81] | ||
Depsipeptide | IC50 value of 50 mM | [82] | ||
Four adipostatins (alkyl resorcinols) potent among the compounds | Kill the worms at 1 mM concentrations | [83] | ||
Crude extract | LC100 62.5 μg/ml | [84] | ||
LC100 500 mg/ml | ||||
Chloroform, n-butanol and aqueous | LC100 250 μg/ml | |||
Fractions of n-hexane oleanonic acid | LC100 31.25 μg/ml | |||
Oleanonic acid | LC100 62.5 μg/ml | |||
Crude extract 1 g/kg × 5 days | 95.05% reduction in Mf 23.65% effective against adult | |||
80% effective against adult | ||||
A001 (crude ethanolic extract of aerial part) F001 (hexane fraction) K003(labda-8(20),13-diene-15-oic acid) and K004 (metasequoic acid A) SF1 (fraction) SF4 (fraction) |
mf (LC100 3.91 μg/ml) than adult worms (LC100 15.63 μg/ml) IC50 values for the respective parasite stages were found to be 1.95 and 10.00 μg/ml mf (LC100 7.83 μg/ml) adult worms (LC100 31.25 μg/ml) mf (LC100 31.25 μg/ml) and adult worms (LC100 125 μg/ml) mf (LC100 7.83 μg/ml) than adult (LC100 31.25 μg/ml) mf (LC100 62.5 μg/ml) adult (LC100 125 μg/ml) |
[85] | ||
A001 (500 mg/kg × 5 days; orally) K003 (100 mg/kg × 5 days) exerted At 100 mg/kg dose, both K003 and K004 K003 (100 mg/kg × 5 days) |
100% effective against Adult >95%; remarkable embryostatic activity Produced >25% macrofilaricidal activity Exerted 53.94% macrofilaricidal |
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Alcoholic extract of flowers Aqueous extract of flowers |
Mf(LC50 of 15 ng/ml) (LC90 ¼ 23 ng/ ml), mf(LC50 of 18 ng/ml) (LC90 ¼ 25 ng/ ml) |
[86, 87, 88] | ||
Methanolic extract of leaves Ethanolic extract of leaves |
Mf 100% mortality at 200 μg/ml in 135 min Mf 90% mortality at 200 μg/ml in 135 min |
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Ethanolic extract of |
Showed significant worm reduction at 25 lg/ml and highest mortality at 100 lg/ml after 24 h of incubation when applied against the microfilariae | |||
Ursolic acid obtained from the leaves | LC100 50 mM and IC50 8.84 mM against microfilariae, and LC100 100 mM and IC50 35.36 mM against adult worms | [89] | ||
Aqueous leaf extract Alcoholic leaf extract |
Both the extracts exhibited macrofilaricidal activity LC50 10 ng/ml and LC90 15 ng/ml LC50 5 ng/ml and LC90 12 ng/ml |
[90] | ||
n-Butanol insoluble fraction of leaf extract | At 250 mg/ml concentration demonstrated a high microfilarial motility | [91] | ||
At a dose of 500 mg/kg × 5 days 1 g/kg × 5 days |
Showed 30% macrofilaricidal activity Showed 57% macrofilaricidal activity |
|||
Methanolic extract of fruit The 2-isopropyl-5-methyl phenol (thymol) was the active component Its positional isomer (i.e., 5-isopropyl-2-methyl phenol, carvacrol,) also showed promising result |
IC50 0.067 and 0.019 mg/ml after 24 h and 48 h, respectively IC50 were 0.024 mg/ml and 0.002 mg/ml after 24 h and 48 h incubation, respectively Macrofilaricidal IC50 values were 0.025 mg/ml and 0.004 mg/ml after 24 h and 48 h incubation, respectively. |
[92] | ||
2-Isopropyl-5-methyl phenol at a dose of 50 mg/ kg for 5 days | Macrofilarial mortality of 58.93% | |||
Galactolipid (n-butanol fraction) obtained from ethanolic extraction of the leaves | The MIC values against adult worms 3.9 mg/ml and 15.6 mg/ml against microfilariae The IC50 values were 1.25 mg/ml and 1.607 mg/ml, respectively, against adult worms and microfilariae |
[93] | ||
50 mg/kg × 5 days | 58.3% adult worm mortality | |||
Crude methanolic at a dose of 100 mg/kg | Suppress mf most effectively and showed 26% efficacy against adult worm | [94] | ||
Active ferulic acid, from the leaves | Approximately 97 and 90%, of reductions in viability of microfilariae and adult worms, respectively | [95] | ||
Crude extract from the seed kernel | 96% macrofilaricidal activity | [96] | ||
The flower extract | Halted the release of mf and worm mobility after 6 days at 1000 mg/ml | [97] | ||
Aqueous–ethanolic extract fruit extract |
IC50 value of 15.46 and 13.17 mg/ml against macrofilariae and microfilariae, respectively | [98] | ||
The ethyl acetate soluble fraction demonstrated | An IC50 value of 8.5 and 6.9 mg ml−1 against macrofilariae and microfilariae, respectively | |||
At a dose of 50 mg/kg for 5 days | 53% macrofilaricidal and 63% embryostatic effects | |||
Gedunin (64) Photogedunin |
Mf (IC50 2.03 mg/ml) Adult (IC50 0.239 mg/ml) Mf (IC50 2.23 mg/ml) Adult (IC50 0.213 mg/ml) |
|||
Gedunin at a dose of 100 mg/kg for 5 days Photogedunin at a dose of 100 mg/kg for 5 days |
Killed 80.0% of the transplanted adult worms 70.0% adult worm mortality |
|||
The root extract |
At a concentration of 100 ng/ml caused a complete loss of microfilarial motility after 48 h of incubation | [99] | ||
Methanolic extracts of |
(IC50) was 0.168 mg/ml | [100] | ||
n-Butanol extract (NBE) of |
Mf (IC50 56.1 μg/ml, (IC50), adult (IC50 57.6 μg/ml) Mf (LD100 187.17 μg/ml) after 24 h of treatment |
[101] | ||
The polyphenol-rich ethanolic extract obtained from the stem part | LD50 values were 2.5, 10 and 35 μg/ml, against the oocytes, microfilariae (Mf) and adults, respectively | [102] | ||
Alcoholic and aqueous extract of fruits of |
LC50 and LC90 were 21 and 35 ng/ml, respectively, for alcoholic, while for aqueous extracts were 27 and 42 ng/ml, respectively | [103] | ||
The crude ethanolic extract from the marine red alga |
LC100 of 62.5 mg ml−1 LC100 of 31.25 mg ml−1 LC100 of 125 mg ml−1 |
[104] | ||
At a dose of 200 mg/kg for 5 days | Exhibited 71.6% 63.2% (ethanolic extract) and 45% (hexane fraction) macrofilaricidal activity, respectively | |||
The methanolic extract Chloroform fraction and its one chromatographic fraction |
Mf (IC50 5 mg/ml) Adult (1.88 mg/ml) Showed antimacrofilarial activity IC50 1.80 mg/ml and 1.62 mg/ml, respectively, whereas concentrations of 1.72 mg/ml and 1.19 mg/ml were effective against microfilariae |
[105] | ||
At a dose of 100 mg/kg for 5 days the methanol extract, chloroform fraction, and chromatographic fraction (contain four major alkaloids: xestospongin-C, araguspongin-C, mimosamycin, and xestospongin-D), respectively | Revealed 51.3%, 64% and 70.7% macrofilaricidal activities in the methanol extract, chloroform fraction, and chromatographic fraction, respectively. | |||
Methanol extract, the n-butanol-soluble fraction Chloroform fraction Araguspongin C |
(LC100 31.25 mg/ml) (LC100 15.6 mg/ml) Macrofilaricidal activity at 15.6 mg/ml |
[106] | ||
The leaf extract from |
IC50 values 62.5 and 31.2 mg/ml, respectively, against adult worms and microfilariae | [107] | ||
At a dose of 100 mg/kg for 5 days | Exhibited 66.7% adulticidal activity and an embryostatic effect | |||
Leaf extracts in different solvents | The methanol extract exhibited more than 80% activity at the highest dose level of 10 mg/ml. The IC50 obtained in methanol extracts are 2.7, 1.96 and 2.58 mg/ml | [108] | ||
The gum extract obtained from In contrast, at a dose of 1000 mg/kg for 5 days |
Mf (LC100 1000 mg/ml) Adult (LC100 125 mg/ml) Mf (IC50 > 1000 mg/ml) Adult (IC50 74.33 mg/ml) Extract showed 69% adulticidal activity and sterilized 83% of the female worms Extract showed 44% adulticidal activity |
[109] | ||
The leaf and root extract Methanol and hexane–ethanol fraction of the leaf extract |
Microfilarial motility in a dose-dependent manner Showed IC50 values of 1.25 and 3.6 mg/ml, respectively, against macrofilariae |
[110, 111] | ||
Methanolic extract of the seed | 90% death in the developmental stages of the parasite | [112, 113, 114] | ||
Rutin and hesperetin | Showed macrofilaricidal activity a 500 mg/ml | |||
Naringenin | Showed macrofilaricidal activity at 125 mg/ml IC50 value at2.5 mg/ml | |||
At 50 mg/kg | Eliminate adult worms 73 and 31%, respectively | |||
Flavone Chrysin |
Exhibit macrofilaricidal activity at 62.5 mg/ml and inhibit the adult motility at 31.2 mg/ml Showed macrofilaricidal activity at 2.50 mg/ml |
8. Role of bioinformatics in filarial research
Bioinformatics is a science of computer-based analysis for the biological datasets in which biology and computer science are mutually helping and influencing each other in the field. Bioinformatics has increased the understanding of molecular mechanism of various cellular processes. Nowadays bioinformatics covers several fields of biological sciences and drug discovery to overcome biological problems.
8.1 Genomic approach in filarial research
Genomic research in bioinformatics is a useful technique used to understand the structure and function of all the genes within an organism. Genomics help to find the particular gene and other biological aspects in the entire genome sequence of the organism. Screening of drug targets can also be done using the genomics approach. Casiraghi et al. [115] had carried out phylogenetic analysis using bioinformatics of 11 filarial and Spirurida nematodes and identified the sequence of mitochondrial cytochrome oxidase-I (COI).
Hoerauf et al. [116] detected the mutual interaction between the intracellular bacteria (endobacteria) and filarial nematodes, which is further used as antifilarial drug targets. Nuchprayoon et al. [117] identified the genetic diversity using phylogenetic analysis parsimony tool (PAUP) between the DNA sequences of two strains of
8.2 Proteomic approach in filarial research
Proteomics approach involved highly efficient methods of protein separation like two-dimensional-poly acrylamide gel electrophoresis (2DPAGE) and detection, using modern tools of bioinformatics. Proteomic analysis of the several stages of
Afterwards Bennuru et al. [119] have also done the same in identifying the excretory/secretory (ES) and somatic proteins of adult, mf, and infective stages of larvae of
Potential inhibitor can be designed on the basis of their binding sites or can be identified from the small-sized molecule databases such as Cambridge Structural Database [123], ChemBank [124], DrugBank [125], PubChem [126], and ZINC database [127] and databases that are available at Lignad.Info: molecule database [128] to inspect the biological activity of the particular protein.
8.3 Web-based available resources for LF
Web-based biological data plays a significant role in bioinformatics which plays a significant role in analyzing biological data for large amount of nucleotide sequences, amino acid sequences, and 2D or 3D structures for the broad range of organisms and their drug targets. Currently, there are only few databases available for LF (Table 6), but the specified database for LF is not available, which is an urgent need in the field of drug development and to overcome the emerging drug resistance. Some of the important databases which are available for LF research have been discussed below.
Name | Description | URL |
---|---|---|
DBEMFDD diseases database | It is an annotated bibliography for filariasis, malaria, dengue, and diarrhea. It also contains the findings of the literature survey | http://ideas.repec.org/p/ess/wpaper/id2032.html |
FilaDB | Database on filaria detection, clinico-immuno monitoring, and management has been developed for Kasturba Hospital and private practitioners to screen the filarial infection | http://www.jbtdrc.org/FilaDb.htm |
NEMBASE2 | Contains the EST sequence for |
http://www.nematodes.org/nematodeESTs/nembase.html |
Filaria Journal | Full and freely access journal of filariasis | http://www.filariajournal.com/ |
Wormbase | It is an online database for the biology and genome of the |
http://www.wormbase.org |
WHO | It contains the related publication of filariasis, reports of elimination program, control of neglected tropical diseases and some important links | http://www.who.int/topics/filariasis/en/ |
PHIS | It contains the news and updated from filariasis elimination program | http://umis.doh.gov.ph/fila |
Disease database | It contains the general information regarding diseases | http://www.diseasesdatabase.com/ddb4824.htm |
TDR-lymphatic filariasis | It contains knowledge about the parasite genomes for African lymphatic filariasis and other diseases TDR is now focusing on providing capacity to use the parasite genome data and on supporting developments in applied genomics and bioinformatics | http://www.who.int/tdrold/diseases/lymphfil/default.htm |
Filarial worms database | This database provides the genome sequence of organisms rapidly and broadly available to the scientific community. | http://www.broadinstitute.org/annotation/genome/filarial_worms/MultiHome.html |
Curated links between genes relevant to filariasis and their sequences in GenBank and Swiss-Prot.
Sequence homology between different filariasis causing genes.
Primary and secondary information of pathogens.
Availability of various drugs and their targets.
Expressed sequence tagged (EST) sequences from different filarial species.
Supporting references from published literatures.
Bioinformatics tools to analyze those data. Database should also contain the epidemiological data on age and gender-wise incidences of disease, remission, and transition rates of disease sequelae.
9. Conclusions
Filariasis is one of the most disabling and disfiguring neglected tropical diseases with various clinical manifestations and a high morbidity rate. Repetitive use of antifilarials has given rise to drug resistance. Most of them are effective against microfilariae and have no effect on the adult worms. Till date numbers of antifilarial targets have been explored, but their evaluation with reference to assay feasibility, target validation, drugability, toxicity, resistance potential, and structural information needs to be discovered in the future. There is a need to explore the mechanism through which drug resistance occurs so that new effective combination therapy could be discovered at an early stage.
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