Abstract:
:A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.
journal_name
PLoS Negl Trop Disjournal_title
PLoS neglected tropical diseasesauthors
Avelar LA,Camilo CD,de Albuquerque S,Fernandes WB,Gonçalez C,Kenny PW,Leitão A,McKerrow JH,Montanari CA,Orozco EV,Ribeiro JF,Rocha JR,Rosini F,Saidel MEdoi
10.1371/journal.pntd.0003916subject
Has Abstractpub_date
2015-07-14 00:00:00pages
e0003916issue
7eissn
1935-2727issn
1935-2735pii
PNTD-D-15-00509journal_volume
9pub_type
杂志文章abstract:BACKGROUND:Plasmodium vivax and Hepatitis B virus (HBV) are globally outspread in similar geographic regions. The concurrence of both infections and its association with some degree of protection against symptomatic and/or severe vivax malaria has been already described. Nevertheless, data on how host response to both ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0007535
更新日期:2019-06-24 00:00:00
abstract:BACKGROUND:Although antibody responses to dengue virus (DENV) in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell responses in relation to clinical disease severity is incompletely understood. METHODOLOGY/PRINCIPAL FINDINGS:Using ex vivo IFNγ ELISpot assays...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0003673
更新日期:2015-04-13 00:00:00
abstract:BACKGROUND:While considerable genomic and transcriptomic data are available for Schistosoma mansoni, many of its genes lack significant annotation. A transcriptomic study of individual tissues and organs of schistosomes could play an important role in functional annotation of the unknown genes, particularly by providin...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001043
更新日期:2011-04-26 00:00:00
abstract::Diarrheal diseases are a major cause of morbidity and mortality worldwide. In many cases, antibiotic therapy is either ineffective or not recommended due to concerns about emergence of resistance. The pathogenesis of several of the most prevalent infections, including cholera and enteroxigenic Escherichia coli, is dom...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0006266
更新日期:2018-02-22 00:00:00
abstract::Entamoeba histolytica, a microaerophilic enteric protozoan parasite, causes amebic colitis and extra intestinal abscesses in millions of inhabitants of endemic areas. Trophozoites of E. histolytica are exposed to a variety of reactive oxygen and nitrogen species during infection. Since E. histolytica lacks key compone...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001831
更新日期:2012-01-01 00:00:00
abstract:BACKGROUND:Lymphatic filariasis (LF), a global public health problem affecting approximately 120 million people worldwide, is a leading cause of disability in the developing world including the South Pacific. Despite decades of ongoing mass drug administration (MDA) in the region, some island nations have not yet achie...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001271
更新日期:2011-08-01 00:00:00
abstract::Snakebites are a major Collective Health problem worldwide. In Brazil, Bothrops jararaca snake venom (BjV) evokes hemostatic disturbances, bleeding manifestations, and redox status imbalance. Specific antivenom therapy, although efficacious to revert most snakebite-induced manifestations, is incapable of treating seco...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0006774
更新日期:2018-10-11 00:00:00
abstract:BACKGROUND:There is a pressing need for drug discovery against visceral leishmaniasis, a life-threatening protozoal infection, as the available chemotherapy is antiquated and not bereft of side effects. Plants as alternate drug resources has rewarded mankind in the past and aimed in this direction, we investigated the ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0007227
更新日期:2019-05-09 00:00:00
abstract::Infection with filarial parasites is associated with T cell hyporesponsiveness, which is thought to be partly mediated by their ability to induce regulatory T cells (Tregs) during human infections. This study investigates the functional capacity of Tregs from different groups of filarial patients to suppress filaria-s...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001655
更新日期:2012-01-01 00:00:00
abstract::In Côte d'Ivoire, rabies is endemic and remains largely uncontrolled. The numbers of human exposures and rabies cases are unknown and are probably much higher than reported. Data on human rabies cases are collected by the National Institute of Public Health (NIPH) Anti-rabies Center in Abidjan through a network of 28 ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0006649
更新日期:2018-09-06 00:00:00
abstract:BACKGROUND:Food and water-borne illness caused by ingestion of (oo)cysts of Cryptosporidium and Giardia is one of the major health problems globally. Several methods are available to detect Giardia cyst and Cryptosporidium oocyst in food and water. Most of the available methods require a good laboratory facility and we...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0008560
更新日期:2020-09-08 00:00:00
abstract:BACKGROUND:Praziquantel-based mass treatment is the main approach to controlling schistosomiasis mansoni in endemic areas. Interventions such as provision and use of safe water, minimising contact with infested water, disposal of stool in latrines and snail control provide key avenues to break the transmission cycle an...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0005982
更新日期:2017-10-02 00:00:00
abstract:BACKGROUND:Leprosy is a Neglected Tropical Diseases (NTDs) known to cause stigma and discrimination in low-and middle-income countries. It often results in visible impairments, thus pre-disposing to poor mental health. Aim of the study was to estimate the prevalence of depression and anxiety among people affected by Le...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0009030
更新日期:2021-01-22 00:00:00
abstract:BACKGROUND:The parasite Onchocerca volvulus has, until recently, been regarded as the cause of a chronic yet non-fatal condition. Recent analyses, however, have indicated that in addition to blindness, the parasite can also be directly associated with human mortality. Such analyses also suggested that the relationship ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001578
更新日期:2012-01-01 00:00:00
abstract:BACKGROUND:Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I) antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001711
更新日期:2012-01-01 00:00:00
abstract::Trachoma, caused by Chlamydia trachomatis (Ct), is the leading infectious blinding disease worldwide. Chronic conjunctival inflammation develops in childhood and leads to eyelid scarring and blindness in adulthood. The immune response to Ct provides only partial protection against re-infection, which can be frequent. ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,评审
doi:10.1371/journal.pntd.0002020
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:Sensitive diagnostic tools are required for an accurate assessment of prevalence and intensity of helminth infections in areas undergoing regular deworming, and for monitoring anthelmintic drug efficacy. We compared the diagnostic accuracy of the Kato-Katz and FLOTAC techniques in the frame of a drug efficac...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001036
更新日期:2011-04-12 00:00:00
abstract:BACKGROUND:Wolbachia inherited intracellular bacteria can manipulate the reproduction of their insect hosts through cytoplasmic incompatibility (CI), and certain strains have also been shown to inhibit the replication or dissemination of viruses. Wolbachia strains also vary in their relative fitness effects on their ho...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0002152
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:The control of neglected tropical diseases (NTDs) has primarily focused on preventive chemotherapy and case management. Less attention has been placed on the role of ensuring access to adequate water, sanitation, and hygiene and personal preventive measures in reducing exposure to infection. Our aim was to a...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,meta分析,评审
doi:10.1371/journal.pntd.0003285
更新日期:2014-11-13 00:00:00
abstract::Patients with mycetoma usually present late with advanced disease, which is attributed to lack of medical and health facilities in endemic areas, poor health education and low socio-economic status. With this background, an integrated patient management model at the village level was designed to address the various pr...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0003271
更新日期:2014-10-30 00:00:00
abstract::Delivery of various forms of recombinant Theileria parva sporozoite antigen (p67) has been shown to elicit antibody responses in cattle capable of providing protection against East Coast fever, the clinical disease caused by T. parva. Previous formulations of full-length and shorter recombinant versions of p67 derived...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0005803
更新日期:2017-08-11 00:00:00
abstract::Canine rabies was endemic pre-urbanisation, yet little is known about how it persists in small populations of dogs typically seen in rural and remote regions. By simulating rabies outbreaks in such populations (50-90 dogs) using a network-based model, our objective was to determine if rabies-induced behavioural change...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0007739
更新日期:2019-09-23 00:00:00
abstract:BACKGROUND:Traditional faecal-based methods have poor sensitivity for the detection of S. stercoralis, therefore are inadequate for post-treatment evaluation of infected patients who should be carefully monitored to exclude the persistence of the infection. In a previous study, we demonstrated high accuracy of five ser...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0003491
更新日期:2015-02-10 00:00:00
abstract:BACKGROUND:Travelers who acquire dengue infection are often routes for virus transmission to other regions. Nevertheless, the interplay between infected travelers, climate, vectors, and indigenous dengue incidence remains unclear. The role of foreign-origin cases on local dengue epidemics thus has been largely neglecte...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0000775
更新日期:2010-08-03 00:00:00
abstract::Humoral immunity plays an important role in controlling dengue virus (DENV) infection. Antibodies (Abs) developed during primary infection protect against subsequent infection with the same dengue serotype, but can enhance disease following secondary infection with a heterologous serotype. A DENV virion has two surfac...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0003564
更新日期:2015-03-11 00:00:00
abstract:OBJECTIVE:Cotrimoxazole prevents opportunistic infections including falciparum malaria in HIV-infected individuals but there are concerns of cross-resistance to other antifolate drugs such as sulphadoxine-pyrimethamine (SP). In this study, we investigated the prevalence of antifolate-resistance mutations in Plasmodium ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,随机对照试验
doi:10.1371/journal.pntd.0007223
更新日期:2019-03-21 00:00:00
abstract::Although several studies have associated Mycobacterium ulcerans (MU) infection, Buruli ulcer (BU), with slow moving water bodies, there is still no definite mode of transmission. Ecological and transmission studies suggest Variable Number Tandem Repeat (VNTR) typing as a useful tool to differentiate MU strains from ot...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0003437
更新日期:2015-01-22 00:00:00
abstract:BACKGROUND:Control and prevention of Chagas disease rely mostly on residual spraying of insecticides. In Argentina, vector control shifted from a vertical to a fully horizontal strategy based on community participation between 1992 and 2004. The effects of such strategy on Triatoma infestans, the main domestic vector, ...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0000363
更新日期:2009-01-01 00:00:00
abstract:BACKGROUND:Mosquito-borne viral diseases cause significant burden in much of the developing world. Although host-virus interactions have been studied extensively in the vertebrate host, little is known about mosquito responses to viral infection. In contrast to mosquitoes of the Aedes and Culex genera, Anopheles gambia...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001565
更新日期:2012-01-01 00:00:00
abstract::West Nile Fever is a zoonotic disease caused by a mosquito-borne flavivirus, WNV. By its clinical sensitivity to the disease, the horse is a useful sentinel of infection. Because of the virus' low-level, short-term viraemia in horses, the primary tools used to diagnose WNV are serological tests. Inter-laboratory profi...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0005936
更新日期:2017-09-15 00:00:00