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BioRxiv : the Preprint Server For... Jun 2024Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the...
Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4 ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E degrader with ABL inhibition while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof-of-concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class antiviral drugs.
PubMed: 38854003
DOI: 10.1101/2024.06.01.596987 -
In silico design of peptide inhibitors for Dengue virus to treat Dengue virus-associated infections.Scientific Reports Jun 2024Dengue virus is a single positive-strand RNA virus that is composed of three structural proteins including capsid, envelope, and precursor membrane while seven...
Dengue virus is a single positive-strand RNA virus that is composed of three structural proteins including capsid, envelope, and precursor membrane while seven non-structural proteins (NS1, NS2A, NS2B, NS3A, NS3B, NS4, and NS5). Dengue is a viral infection caused by the dengue virus (DENV). DENV infections are asymptomatic or produce only mild illness. However, DENV can occasionally cause more severe cases and even death. There is no specific treatment for dengue virus infections. Therapeutic peptides have several important advantages over proteins or antibodies: they are small in size, easy to synthesize, and have the ability to penetrate the cell membranes. They also have high activity, specificity, affinity, and less toxicity. Based on the known peptide inhibitor, the current study designs peptide inhibitors for dengue virus envelope protein using an alanine and residue scanning technique. By replacing I21 with Q21, L14 with H14, and V28 with K28, the binding affinity of the peptide inhibitors was increased. The newly designed peptide inhibitors with single residue mutation improved the binding affinity of the peptide inhibitors. The inhibitory capability of the new promising peptide inhibitors was further confirmed by the utilization of MD simulation and free binding energy calculations. The molecular dynamics simulation demonstrated that the newly engineered peptide inhibitors exhibited greater stability compared to the wild-type peptide inhibitors. According to the binding free energies MM(GB)SA of these developed peptides, the first peptide inhibitor was the most effective against the dengue virus envelope protein. All peptide derivatives had higher binding affinities for the envelope protein and have the potential to treat dengue virus-associated infections. In this study, new peptide inhibitors were developed for the dengue virus envelope protein based on the already reported peptide inhibitor.
Topics: Dengue Virus; Peptides; Dengue; Antiviral Agents; Humans; Drug Design; Molecular Dynamics Simulation; Viral Envelope Proteins; Computer Simulation; Protein Binding
PubMed: 38849372
DOI: 10.1038/s41598-024-63064-1 -
PLoS Neglected Tropical Diseases Jun 2024A group of children with clinical suspicion of dengue were assessed to determine if there was an overestimation of dengue compared with that of leptospirosis and... (Comparative Study)
Comparative Study
A group of children with clinical suspicion of dengue were assessed to determine if there was an overestimation of dengue compared with that of leptospirosis and leishmaniasis. This descriptive and analytical cross-sectional study, based on the active search of participants with acute febrile illness, was conducted at two pediatric hospitals. The collection of clinical and epidemiological data was performed using questionnaires, and laboratory tests specific for dengue were performed using immunochromatographic, serological, and molecular methods. Dengue-negative samples were assessed for Leptospira and Leishmania spp. using molecular tests. Data were assessed using analysis of variance (ANOVA), the chi-square test, and Fisher's exact test. In total, 86 participants were evaluated, of whom 39 (45%) were positive for dengue fever, 4 (5%) for leptospirosis, and 1 (1%) for leishmaniasis. Forty-two participants (49%) presented dengue-like symptoms. The predominant age range for the virus was 3-10 years. Most clinical manifestations were nonspecific, with frequent concomitant gastrointestinal and respiratory symptoms. Furthermore, we found that the acute febrile syndrome in childhood persists as a challenge for health professionals, especially in the early days of the disease, due to a plurality of diagnostic hypotheses, associated with the difficulty of establishing well-defined symptoms in children, especially in infants. Dengue fever continues to be a frequent pathology with acute febrile infections in childhood; however, there is an overestimation of the disease, especially in endemic regions, when one considers only the clinical epidemiological diagnosis.
Topics: Humans; Dengue; Male; Female; Cross-Sectional Studies; Child, Preschool; Child; Fever; Infant; Leptospirosis; Adolescent
PubMed: 38848319
DOI: 10.1371/journal.pntd.0012137 -
Microbiology Spectrum Jun 2024
PubMed: 38847546
DOI: 10.1128/spectrum.00701-24 -
Lancet Regional Health. Americas Jul 2024This study focuses on urban arboviruses, specifically dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV), which pose a significant public health challenge in Rio de...
BACKGROUND
This study focuses on urban arboviruses, specifically dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV), which pose a significant public health challenge in Rio de Janeiro state, Southeast Brazil. In our research, we highlight critical findings on the transmission dynamics of these arboviruses in Rio de Janeiro, identifying distinct patterns of disease spread.
METHODS
By combining genomic data with case reports from the Brazilian Ministry of Health, we have analysed the phylogenetics, prevalence and spatial distribution of these endemic viruses within the state.
FINDINGS
Our results revealed sustained DENV transmission primarily in the northern part of the state, a significant ZIKV epidemic in 2016 affecting all mesoregions, and two major CHIKV outbreaks in 2018 and 2019, predominantly impacting the northern and southern areas. Our analysis suggests an inverse relationship between arboviral case incidence and urban density, with less populous regions experiencing higher transmission rates, potentially attributed to a complex interplay of factors such as the efficacy of vector control measures, environmental conditions, local immunity levels, and human mobility. Furthermore, our investigation unveiled distinct age and gender trends among affected individuals. Notably, dengue cases were predominantly observed in young adults aged 32, while chikungunya cases were more prevalent among individuals over 41. In contrast, cases of ZIKV were concentrated around the 33-year age group. Intriguingly, females accounted for nearly 60% of the cases, suggesting a potential gender-based difference in infection rates.
INTERPRETATION
Our findings underscore the complexity of arbovirus transmission and the need for interventions tailored to different geographical mesoregions. Enhanced surveillance and genomic sequencing will be essential for a deeper, more nuanced understanding of regional arbovirus dynamics. Identifying potential blind spots within the state will be pivotal for developing and implementing more effective public health strategies, specifically designed to address the unique challenges posed by these viruses throughout the state.
FUNDING
This study was supported by the National Institutes of Health USA grant U01 AI151698 for the United World Arbovirus Research Network (UWARN) and the CRP-ICGEB RESEARCH GRANT 2020 Project CRP/BRA20-03.
PubMed: 38846808
DOI: 10.1016/j.lana.2024.100786 -
Medecine Tropicale Et Sante... Mar 2024The Republic of Djibouti is located in the Horn of Africa, on the Gulf of Aden and the Bab-el-Mandeb detroit, at the southern entrance to the Red Sea. Prior to its... (Review)
Review
BACKGROUND AND JUSTIFICATION
The Republic of Djibouti is located in the Horn of Africa, on the Gulf of Aden and the Bab-el-Mandeb detroit, at the southern entrance to the Red Sea. Prior to its independence in 1977, the Republic of Djibouti was known by two names: "Côte française des Somalis" until 1967, then "Territoire Français de Afars et Issas". As part of our doctoral research on the ecology of mosquitoes in Djibouti, we noted a lack of information on the species encountered, and felt it essential to draw up a list of species before embarking on ecological monitoring. The aim of this work is to survey publications on mosquitoes in Djibouti and to synthesize data from this scientific literature in order to update the national inventory of Culicidae.
MATERIALS AND METHODS
An exhaustive search of electronic bibliographic databases (PubMed, Scopus, HAL Open Archive, Science Direct and Google Scholar) was carried out. Reference lists were filtered to access additional articles in order to obtain more data. Two keywords were used: "Djibouti" and "French Territory of Afars and Issas". A selection of scientific publications on Djibouti mosquitoes and/or diseases transmitted by mosquito vectors was made. Researches were conducted in articles selected. The names of the species listed were checked and validated by referring to the site Mosquito Taxonomic Inventory.
RESULTS
A total of 13 studies, published between 1970 and 2023, were found. Over the years, the composition of the Culicidae fauna has become well known. In part, the movement of people traveling to and from neighboring countries has been linked to the detection of new species and the reappearance of mosquito species in Djibouti. Numerous studies have been carried out over the years, including purely taxonomic studies and others focusing on the incrimination of mosquito vectors and the characterization of the pathogens they transmit. A total of 37 species, belonging to two subfamilies (Anophelinae and Culicinae), of mosquitoes divided between 7 genera and have been mentioned across the country. The number of species per genus is distributed as follows: 5 species of including 1 subspecies, 14 species of including two subspecies, 12 species of including 1 subspecies, 1 species for each of the genera and and finally 2 species respectively for the genera and Five species have been incriminated as vectors of diseases such as malaria, dengue fever, yellow fever, West Nile virus and chikungunya. Others are known for their potential role in pathogen transmission, including Zika and Rift Valley virus.
DISCUSSION - CONCLUSION
The bibliographical research enabled us to summarize the research carried out over more than half a century in the history of Djibouti, and to update the inventory of the country's mosquitoes, which now includes 37 species. Species names were reviewed and updated, and the case of was also addressed. Two species mentioned as part of the Culicidae fauna of Djibouti appeared to be doubtful and are up for discussion. These results provide a useful information base for defining vector control priorities in Djibouti. They will also inform, guide and facilitate future consultations of our database. In addition, this study will help to identify research ways on mosquitoes in Djibouti.
Topics: Animals; Culicidae; Djibouti; Mosquito Vectors
PubMed: 38846112
DOI: 10.48327/mtsi.v4i1.2024.365 -
Health Science Reports Jun 2024In context, the dengue virus causes dengue fever, which is spread by mosquito bites. About 22,000 people every year lose their lives as a direct result of it. Dengue...
BACKGROUND
In context, the dengue virus causes dengue fever, which is spread by mosquito bites. About 22,000 people every year lose their lives as a direct result of it. Dengue fever has been on the rise recently, and its spread has alarmed health officials throughout the world.
DISCUSSION
Vaccination is essential for the prevention and management of dengue cases because there is currently no particular cure against dengue virus. The current dengue epidemic calls for urgent action in the form of immunization. However, there are serious drawbacks to using existing vaccines like Dengvaxia. Besides, the Qdenga vaccine has not yet been approved by the FDA in the United States. On the other hand, positive results from a phase II randomized and controlled clinical study of the TV005 tetravalent live-attenuated dengue vaccine were recently reported in Bangladesh. Only an effective vaccination can drastically lower dengue infection and mortality rates.
CONCLUSION
The development of safe and effective vaccination, as well as their correct dissemination, is an essential requirement for the people of Bangladesh and the rest of the globe, and we concentrated on this critical problem in this article.
PubMed: 38845788
DOI: 10.1002/hsr2.2170 -
PloS One 2024In dengue-endemic areas, transmission control is limited by the difficulty of achieving sufficient coverage and sustainability of interventions. To maximize the...
In dengue-endemic areas, transmission control is limited by the difficulty of achieving sufficient coverage and sustainability of interventions. To maximize the effectiveness of interventions, areas with higher transmission could be identified and prioritized. The aim was to identify burden clusters of Dengue virus (DENV) infection and evaluate their association with microclimatic factors in two endemic towns from southern Mexico. Information from a prospective population cohort study (2·5 years of follow-up) was used, microclimatic variables were calculated from satellite information, and a cross-sectional design was conducted to evaluate the relationship between the outcome and microclimatic variables in the five surveys. Spatial clustering was observed in specific geographic areas at different periods. Both, land surface temperature (aPR 0·945; IC95% 0·895-0·996) and soil humidity (aPR 3·018; IC95% 1·013-8·994), were independently associated with DENV burden clusters. These findings can help health authorities design focused dengue surveillance and control activities in dengue endemic areas.
Topics: Humans; Dengue; Mexico; Female; Male; Dengue Virus; Microclimate; Cross-Sectional Studies; Adult; Adolescent; Prospective Studies; Child; Endemic Diseases; Young Adult; Middle Aged; Child, Preschool; Humidity; Cluster Analysis; Temperature
PubMed: 38843173
DOI: 10.1371/journal.pone.0302025 -
Scientific Data Jun 2024Aedes aegypti is a primary vector for transmitting various arboviruses, including Yellow fever, dengue and Zika virus. The mosquito midgut is the principal organ for...
Aedes aegypti is a primary vector for transmitting various arboviruses, including Yellow fever, dengue and Zika virus. The mosquito midgut is the principal organ for blood meal digestion, nutrient absorption and the initial site of arbovirus infection. Although a previous study delineated midgut's transcriptome of Ae. aegypti at the single-nucleus resolution, there still lacks an established protocol for isolating and RNA sequencing of single cells of Ae. aegypti midgut, which is required for investigating arbovirus-midgut interaction at the single-cell level. Here, we established an atlas of the midgut cells for Ae. aegypti by single-cell RNA sequencing. We annotated the cell clusters including intestinal stem cells/enteroblasts (ISC/EB), cardia cells (Cardia), enterocytes (EC, EC-like), enteroendocrine cells (EE), visceral muscle (VM), fat body cells (FBC) and hemocyte cells (HC). This study will provide a foundation for further studies of arbovirus infection in mosquito midgut at the single-cell level.
Topics: Animals; Aedes; Single-Cell Analysis; Female; Sequence Analysis, RNA; Transcriptome; Gastrointestinal Tract; Mosquito Vectors; Digestive System
PubMed: 38839790
DOI: 10.1038/s41597-024-03432-8 -
Archives of Virology Jun 2024Monocytes are the primary targets of Zika virus (ZIKV) and are associated with ZIKV pathogenesis. Currently, there is no effective treatment for ZIKV infection. It is...
Monocytes are the primary targets of Zika virus (ZIKV) and are associated with ZIKV pathogenesis. Currently, there is no effective treatment for ZIKV infection. It is known that 1,25-dihydroxy vitamin D (VitD3) has strong antiviral activity in dengue virus-infected macrophages, but it is unknown whether VitD3 inhibits ZIKV infection in monocytes. We investigated the relationship between ZIKV infection and the expression of genes of the VitD3 pathway, as well as the inflammatory response of infected monocytes in vitro. ZIKV replication was evaluated using a plaque assay, and VitD3 pathway gene expression was analyzed by RT-qPCR. Pro-inflammatory cytokines/chemokines were quantified using ELISA. We found that VitD3 did not suppress ZIKV replication. The results showed a significant decrease in the expression of vitamin D3 receptor (VDR), cytochrome P450 family 24 subfamily A member 1 (CYP24A1), and cathelicidin antimicrobial peptide (CAMP) genes upon ZIKV infection. Treatment with VitD3 was unable to down-modulate production of pro-inflammatory cytokines, except TNF-α, and chemokines. This suggests that ZIKV infection inhibits the expression of VitD3 pathway genes, thereby preventing VitD3-dependent inhibition of viral replication and the inflammatory response. This is the first study to examine the effects of VitD3 in the context of ZIKV infection, and it has important implications for the role of VitD3 in the control of viral replication and inflammatory responses during monocyte infection.
Topics: Humans; Antimicrobial Cationic Peptides; Cathelicidins; Cytokines; Monocytes; Receptors, Calcitriol; Virus Replication; Vitamin D3 24-Hydroxylase; Zika Virus; Zika Virus Infection
PubMed: 38839691
DOI: 10.1007/s00705-024-06050-2