scholarly journals Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture

2019 ◽  
Author(s):  
Markos Tadele ◽  
Solomon M. Abay ◽  
Eyasu Makonnen ◽  
Asrat Hailu
Keyword(s):  
Drug Discovery ◽  
Visceral Leishmaniasis ◽  
Drug Development ◽  
Leishmania Donovani ◽  
Inhibitory Concentration ◽  
Public Health Problem ◽  
Neglected Diseases ◽  
Major Public Health Problem ◽  
New Chemical Entities ◽  
Intracellular Amastigote

AbstractLeishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given low attention in drug discovery researches to narrow the existing gap in safety and efficacy of the currently used drugs to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Aiming to look for potential anti-leishmanial hits and leads, we screened MMV Pathogen Box against clinically isolated L. donovani strain. Compounds were screened against promastigote, and then against amastigote stages; of which, 35 compounds showed >50% inhibition on promastigotes in the initial screen (1 μM). Out of these compounds, 9 compounds showed >70% inhibition with median inhibitory concentration (IC50) ranges from 12 nM to 491 nM on anti-promastigote assay and 53 to 704 nM on intracellular amastigote assay. Identified compounds demonstrated good safety on THP-1 cell lines and sheep RBCs, and appropriate physico-chemical property suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as lead compounds. Among these compounds, anti-tubercular agent MMV688262 (delamanid) showed synergistic effect with amphotericin B, indicating the prospect of this compound for combination therapy. The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure activity relationship studies. Future works also needs to investigate antiamastigotes activity of remaining ‘hits’, which were not covered in the present study.Authors summaryVisceral leishmaniasis is a major public health problem in endemic regions. Different drugs have been used to treat visceral leishmaniasis. However, the available drugs are either toxic, non-compliance to the patient, painful upon administration, low in efficacy, or costly. New chemical entities that overcome the limitations of existing drugs are therefore desperately needed. Screening of 400 pathogen box compounds against of Leishmania donovani clinical isolate resulted in identification of 35 compounds with >50% inhibition against promastigotes at 1 μM. Out of these compounds, 9 showed >70% inhibition with median inhibitory concentration ranges from 12 nM to 491 nM on anti-promastigote assay, and 53 to 704 nM on intracellular amastigote assay. Our work identified new compounds which hold promise for further drug development.

scholarly journals Comparative Study of Microscopy and Polymerase Chain Reaction for the Diagnosis of Suspected Visceral Leishmaniasis Patients in Nepal

2014 ◽  
Vol 11 (1) ◽  
pp. 14-17 ◽  
Author(s):  
K Pandey ◽  
AK Mallik ◽  
S Pyakurel ◽  
SB Pun ◽  
BD Pandey
Keyword(s):  
Bone Marrow ◽  
Polymerase Chain Reaction ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Polymerase Chain Reaction Amplification ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Endemic Areas

Background Visceral leishmaniasis is potentially fatal protozoan diseases caused by Leishmania donovani. Nepal is an endemic region in which visceral leishmaniasis causes a major public health problem in the lowland areas that border the endemic areas of Bihar state in India. Accurate diagnosis to inform treatment is a first step in achieving the goal of visceral leishmaniasis elimination from South East Asian regions by 2020. Objective The objective of the present study was to compare between the Microcopy and polymerase chain reaction for diagnosis of visceral leishmaniasis. Methods In the present study, 236 bone marrow aspirations were collected from suspected visceral leishmaniasis patients in Janakpur Zonal Hospital, Dhanusa district, Terai region of Nepal in between 2003-2007. We evaluated bone marrow samples by microscopic examination with subsequent testing of the same sample by polymerase chain reaction and sequence analysis. Results Giemsa’s solution stained bone marrow slides stored for over five years were used for polymerase chain reaction amplification. The result showed that 71% were polymerase chain reaction positive and 56% were microscopic positive. Out of 104 microscopic negative bone marrow samples, 15% of samples were positive by polymerase chain reaction. Conclusion Polymerase chain reaction could make a very good option for diagnosis by using less or non-invasive material from visceral leishmaniasis patients in endemic areas of Nepal. DOI: http://dx.doi.org/10.3126/kumj.v11i1.11016 Kathmandu University Medical Journal Vol.11(1) 2013: 14-17

scholarly journals Slow pace of antileishmanial drug development

2018 ◽  
Vol 4 ◽  
Author(s):  
Awanish Kumar ◽  
Satish Chandra Pandey ◽  
Mukesh Samant
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Drug Targets ◽  
Leishmania Donovani ◽  
Protozoan Parasite ◽  
Effective Vaccine ◽  
Neglected Diseases ◽  
Major Barrier ◽  
Slow Pace ◽  
Antileishmanial Drug

AbstractThe protozoan parasiteLeishmaniais endemic in large parts of the world which causes leishmaniasis. Its visceral form is fatal if not treated and is caused mostly byLeishmania donovani,Leishmania infantumandLeishmania chagasi. Given the difficulties linked to vector (sandfly) control and the lack of an effective vaccine, the control of leishmaniasis relies mostly on chemotherapy. Unfortunately, the prevalence of parasites becoming resistant to the first-line drug pentavalent antimony (SbV) is increasing worldwide. Few alternative drugs are available that includes amphotericin B, pentamidine and miltefosine (oral). Already, decreases in efficacy, resistance and toxicity have been noted against these drugs. Dry antileishmanial pipeline further indicates the slow pace of drug discovery in this field where resistance as a major barrier. Full understanding of the genetic and molecular basis of the parasite is lagging. Since leishmaniasis is a neglected disease and occurs predominantly in the developing world largely, therefore, it is unaddressed. The pharma industry argues that development of the new drug is too costly and risky to invest in low return neglected diseases is very high. Research is also needed to identify new and effective drug targets. The lack of drug research and development for neglected diseases will require some new strategies. We have discussed the various cause of slow pace of antileishmanial drug discovery in this review to pay attention of researchers and also take the public and private initiative to make the process fast for new antileishmanial drug development.

scholarly journals Development of Vaccines against Visceral Leishmaniasis

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Krystal J. Evans ◽  
Lukasz Kedzierski
Keyword(s):  
Public Health ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Clinical Symptoms ◽  
Public Health Problem ◽  
Past Infection ◽  
Health Goal ◽  
Disability Adjusted Life ◽  
Life Years ◽  
Public Health Goal

Leishmaniasis is a neglected disease resulting in a global morbidity of 2,090 thousand Disability-Adjusted Life Years and a mortality rate of approximately 60,000 per year. Among the three clinical forms of leishmaniasis (cutaneous, mucosal, and visceral), visceral leishmaniasis (VL) accounts for the majority of mortality, as if left untreated VL is almost always fatal. Caused by infection withLeishmania donovaniorL. infantum, VL represents a serious public health problem in endemic regions and is rapidly emerging as an opportunistic infection in HIV patients. To date, no vaccine exists for VL or any other form of leishmaniasis. In endemic areas, the majority of those infected do not develop clinical symptoms and past infection leads to robust immunity against reinfection. Thus the development of vaccine forLeishmaniais a realistic public health goal, and this paper summarizes advances in vaccination strategies against VL.

scholarly journals Improved Performance of ELISA and Immunochromatographic Tests Using a New Chimeric A2-Based Protein for Human Visceral Leishmaniasis Diagnosis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Maria Marta Figueiredo ◽  
Anna R. R. dos Santos ◽  
Lara C. Godoi ◽  
Natália S. de Castro ◽  
Bruno C. de Andrade ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Chimeric Protein ◽  
Public Health Problem ◽  
Control Measures ◽  
Major Public Health Problem ◽  
Human Visceral Leishmaniasis ◽  
Healthy Donors ◽  
Improved Performance ◽  
Sensitivity Specificity ◽  
Sera Samples

Summary. Human visceral leishmaniasis (VL) is a major public health problem worldwide, leading to significant mortality rates if not properly treated and controlled. Precise identification of infected patients is essential to establish treatment and control measures. Although several VL serological diagnosis advances have been accomplished lately, mainly using recombinant antigens and immunochromatographic tests (ICTs), improvements may still be achieved using multiepitope chimeric proteins in different test platforms. Here, we reported on the evaluation of ELISA and an ICT developed with a new chimeric protein, named DTL-4, based on repetitive antigenic sequences, including those present in the A2 protein. Methods. A total of 1028 sera samples were used for the development and validation of ELISA (321 samples from L. infantum-infected patients, 62 samples from VL/AIDS coinfected patients, 236 samples from patients infected with other diseases, and 409 samples from healthy donors). A total of 520 sera samples were used to develop and validate ICT (249 samples from L. infantum-infected patients, 46 samples from VL/AIDS coinfected patients, 40 samples from patients infected with other diseases, and 185 samples from healthy donors). Findings. Using the validation sera panels, DTL-4-based ELISA displayed an overall sensitivity of 94.61% (95% CI: 89.94-97.28), a specificity of 99.41% (95% CI: 96.39-99.99), and an accuracy of 97.02% (95% CI: 94.61-98.38), while for ICT, sensitivity, specificity, and accuracy values corresponded to 91.98% (95% CI: 86.65-95.39), 100.00% (95% CI: 96.30-100.00), and 95.14% (95% CI: 91.62-97.15), respectively. When testing sera samples from VL/AIDS coinfected patients, DTL-4-ELISA displayed a sensitivity of 77.42% (95% CI: 65.48-86.16), a specificity of 99.41% (95% CI: 96.39-99.99), and an accuracy of 93.51% (95% CI: 89.49%-96.10%), while for DTL-4-ICT, sensitivity was 73.91% (95% CI: 59.74-84.40), specificity was 90.63% (95% CI: 81.02-95.63), and accuracy was 82.00% (95% CI: 73.63-90.91). Conclusion. DTL-4 is a promising candidate antigen for serodiagnosis of VL patients, including those with VL/AIDS coinfection, when incorporated into ELISA or ICT test formats.

scholarly journals Systematic Review of Visceral Leishmaniasis in Central Africa

2021 ◽  
pp. 8-20
Author(s):  
Demba Kodindo Israël ◽  
Cheick Amadou Coulibaly ◽  
John C. Beier ◽  
Gunter C. Muller ◽  
Seydou Doumbia
Keyword(s):  
Public Health ◽  
Visceral Leishmaniasis ◽  
Central Africa ◽  
Public Health Problem ◽  
Severe Form ◽  
Canine Leishmaniasis ◽  
Neglected Diseases ◽  
Kala Azar ◽  
Public Health Challenges ◽  
Significant Public Health

In underdeveloped countries, infectious diseases remain one of the most important public health challenges. Visceral leishmaniasis, also known as Kala-azar, is a lethal vector-borne parasitic disease with an increasing number of cases. However, it remains one of the most neglected diseases in the world. It is the most severe form of leishmaniasis and is endemic in 75 countries. Around 95% of the patients live in seven countries: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan, and causes about 20,000-40,000 deaths per year of which 50-70% are children. In Central Africa, this pathology is little known and less documented, making it difficult to access information. We have performed this study to characterize the knowledge on the epidemiology of visceral leishmaniasis in Central Africa. We reviewed the literature on visceral leishmaniasis in Central Africa on the number of reported cases, identified parasites, reservoirs and vectors. The documents consulted came from WHO reports, publications of scientific journals, reports of research institutions and abstracts of scientific conferences consulted online on Pubmed and Google Scholar. The information covers the period from the first reporting of cases in each country until December 2020. The review of the situation of visceral leishmaniasis revealed that it is not a significant public health problem in Central Africa. However, a lot of work remains to be done especially surveillance and research in order to present the exact situation of the disease in this part of the continent. This work would include the underreporting of cases inherent to the weaknesses of the surveillance system in these countries, the clarification of the transmission dynamics of human visceral leishmaniasis, canine leishmaniasis, the identity of parasites and vectors.

The Leishmanioses

2011 ◽  
Author(s):  
Marina Gramiccia
Keyword(s):  
South America ◽  
Cutaneous Lesion ◽  
Public Health Problem ◽  
Leishmania Species ◽  
Neglected Diseases ◽  
Major Public Health Problem ◽  
Phlebotomine Sandflies ◽  
Wide Range ◽  
Behavioural Factors ◽  
Visceral Leishmaniosis

Leishmanioses are a large group of parasitic diseases range over the intertropical zones of America and Africa, and extend into temperate regions of South America, Southern Europe and Asia. The clinical aspect of the diseases is wide ranging from a simple, self-resolving cutaneous lesion to the potentially fatal visceral leishmaniosis, known as kala-azar. In numerous underdeveloped countries leishmanioses remain a major public health problem representing one of the most neglected diseases. Among 15 well-recognized Leishmania species known to infect humans, 13 have definite zoonotic nature, which include agents of visceral, cutaneous and mucocutaneous forms of the disease in both the Old and New Worlds. Mammal reservoir hosts belong to the marsupalia, edentata, carnivora, hyracoidea, and rodentia, maintaining sylvatic zoonotic foci in the deserts of Africa and Asia, the forests of South and Central America, as well as synanthropic foci in the Mediterranean basin and much of South America. Although the known vectors are all phlebotomine sandflies, these have a wide range of specific habits and habitats. The complexity of this group of infections has only recently been appreciated and is still being worked out. Currently, leishmanioses show a wider geographical distribution than previously known, with increased global incidence of human disease. Environmental, demographic and human behavioural factors contribute to the changing leishmaniosis landscape, which basically include increasing risk factors for zoonotic cutaneous leishmanioses, and new scenarios associated with the zoonotic entity of visceral leishmaniosis. In comparison with the anthroponotic entities of leishmaniosis, limited progresses were made for the control of the zoonotic ones, consisting mainly in new tools developed for the control of L. infantum in the canine reservoir.

scholarly journals Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

2016 ◽  
Vol 60 (4) ◽  
pp. 2484-2491 ◽  
Author(s):  
A. K. Marr ◽  
S. Cen ◽  
R. E. W. Hancock ◽  
W. R. McMaster
Keyword(s):  
Host Defense ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Host Defense Peptides ◽  
Content Type ◽  
Leishmanicidal Activity ◽  
Wide Range ◽  
Defense Peptides

ABSTRACTLeishmaniaparasites are a major public health problem worldwide. Effective treatment of leishmaniasis is hampered by the high incidence of adverse effects to traditional drug therapy and the emergence of resistance to current therapeutics. A vaccine is currently not available. Host defense peptides have been investigated as novel therapeutic agents against a wide range of pathogens. Here we demonstrate that the antimicrobial peptide LL-37 and the three synthetic peptides E6, L-1018, and RI-1018 exhibit leishmanicidal activity against promastigotes and intramacrophage amastigotes ofLeishmania donovaniandLeishmania major. We also report that theLeishmaniaprotease/virulence factor GP63 confers protection toLeishmaniafrom the cytolytic properties of alll-form peptides (E6, L-1018, and LL-37) but not thed-form peptide RI-1018. The results suggest that RI-1018, E6, and LL-37 are promising peptides to develop further into components for antileishmanial therapy.

scholarly journals Spatial analysis ofLeishmania donovaniexposure in humans and domestic animals in a recent kala azar focus in Nepal

Parasitology ◽  
2010 ◽  
Vol 137 (11) ◽  
pp. 1597-1603 ◽  
Author(s):  
BASUDHA KHANAL ◽  
ALBERT PICADO ◽  
NARAYAN RAJ BHATTARAI ◽  
GERT VAN DER AUWERA ◽  
MURARI LAL DAS ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Public Health Problem ◽  
Domestic Animals ◽  
Major Public Health Problem ◽  
Scan Statistic ◽  
Transmission Cycle ◽  
Kala Azar ◽  
Information System Technology

SUMMARYVisceral leishmaniasis (VL) is a major public health problem in the Indian subcontinent where theLeishmania donovanitransmission cycle is described as anthroponotic. However, the role of animals (in particular domestic animals) in the persistence and expansion of VL is still a matter of debate. We combined Direct Agglutination Test (DAT) results in humans and domestic animals with Geographic Information System technology (i.e. extraction maps and scan statistic) to evaluate the exposure toL. donovanion these 2 populations in a recent VL focus in Nepal. A Poisson regression model was used to assess the risk of infection in humans associated with, among other factors, the proportion of DAT-positive animals in the proximities of the household. The serological results showed that both humans and domestic animals were exposed toL. donovani. DAT-positive animals and humans were spatially clustered. The presence of serologically positive goats (IRR=9·71), past VL cases (IRR=2·62) and the proximity to a forest island dividing the study area (IRR=3·67) increased the risk of being DAT-positive in humans. Even if they are not a reservoir, domestic animals, and specially goats, may play a role in the distribution ofL. donovani, in particular in this new VL focus.

scholarly journals Sandfly fauna in an area endemic for visceral leishmaniasis in Aracaju, State of Sergipe, Northeast Brazil

2012 ◽  
Vol 45 (3) ◽  
pp. 318-322 ◽  
Author(s):  
Verónica de Lourdes Sierpe Jeraldo ◽  
Marco Aurélio de Oliveira Góes ◽  
Claudio Casanova ◽  
Claudia Moura de Melo ◽  
Edilson Divino de Araújo ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Rural Area ◽  
Urban Areas ◽  
Uv Light ◽  
Public Health Problem ◽  
Ultra Violet ◽  
Abundant Species ◽  
Lutzomyia Longipalpis ◽  
Major Public Health Problem ◽  
Phlebotomine Sandflies

INTRODUCTION: In recent years, visceral leishmaniasis, a major public health problem, has been spreading from the rural to urban areas in many areas of Brazil, including Aracaju, the capital of the State of Sergipe. However, there are no studies of the sandfly fauna in this municipality or its variation over the year. METHODS: Phlebotomine sandflies were collected from a rural area of Aracaju from September 2007 to July 2009. Modified CDC ultra-violet (UV) light traps were used to evaluate sandfly monthly distribution and their presence in the domestic and peridomestic environments. RESULTS: The most abundant species was Lutzomyia longipalpis (90.4%) followed by Evandromyia lenti (9.6%). A chicken shed trap site had the highest proportion of L. longipalpis (51.1%) and large numbers of L. longipalpis were also collected in the houses closest to the chicken shed. There was a positive correlation between monthly rainfall and L. longipalpis abundance. CONCLUSIONS: Lutzomyia longipalpis is the most abundant species and is probably the main vector of the visceral leishmaniasis agent in the rural area of Aracaju. An increase in L. longipalpis frequency was observed during the rainy season. The peridomicile-intradomicile observations corroborate the importance of chicken sheds for the presence of L. longipalpis in the peridomestic environment. The great numbers of L. longipalpis inside the houses confirm the endophilic behaviour of this species and the possibility of visceral transmission in the intradomicile.

scholarly journals Identification of Vaccine Candidates for Experimental Visceral Leishmaniasis by Immunization with Sequential Fractions of a cDNA Expression Library

2000 ◽  
Vol 68 (10) ◽  
pp. 5595-5602 ◽  
Author(s):  
Peter C. Melby ◽  
Gary B. Ogden ◽  
Hector A. Flores ◽  
Weiguo Zhao ◽  
Christopher Geldmacher ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Cdna Library ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Public Health Problem ◽  
Cdna Expression Library ◽  
Sequential Fractionation ◽  
Expression Library ◽  
Vaccine Candidates

ABSTRACT Visceral leishmaniasis caused by the intracellular parasiteLeishmania donovani is a significant public health problem in many regions of the world. Because of its large genome and complex biology, developing a vaccine for this pathogen has proved to be a challenging task and, to date, protective recombinant vaccine candidates have not been identified. To tackle this difficult problem, we adopted a reductionist approach with the intention of identifying cDNA sequences in an L. donovani amastigote cDNA library that collectively or singly conferred protection against parasite challenge in a murine model of visceral leishmaniasis. We immunized BALB/c mice with plasmid DNA isolated and pooled from 15 cDNA sublibraries (∼2,000 cDNAs/sublibrary). Following systemic challenge with L. donovani, mice immunized with 6 of these 15 sublibraries showed a significantly reduced (35- to 1,000-fold) hepatic parasite burden. Because of the complexity and magnitude of the sequential fractionation-immunization-challenge approach, we restricted our attention to the two sublibraries that conferred the greatest in vivo protection. From one of these two sublibraries, we identified several groups of cDNAs that afforded protection, including a set of nine novel cDNAs and, surprisingly, a group of five cDNAs that encoded L. donovani histone proteins. At each fractionation step, the cDNA sublibraries or the smaller DNA fractions that afforded in vivo protection against the parasite also induced in vitro parasite-specific T helper 1 immune responses. Our studies demonstrate that immunization with sequential fractions of a cDNA library is a powerful strategy for identifying anti-infective vaccine candidates.

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