Visualizing and Analyzing the Chemical Space of Natural Product Databases for Drug Discovery.

Chemical space is a multidimensional descriptor space that encloses all possible molecules, and at least 1 x 1060 organic substances with a molecular weight below 500 Da are thought to be potentially relevant for drug discovery. Natural products have been the primary source of the new pharmacological entities marketed during the past forty years and continue to be one of the most productive sources for the creation of innovative medications. Chemoinformatics-based computational tools accelerate the drug development process for natural products. Methods including estimating bioactivities, safety profiles, ADME, and natural product likeness measurement have been used. Here, we go over recent developments in chemoinformatic tools designed to visualize, characterize, and expand the chemical space of natural compound data sets using various molecular representations, create visual representations of such spaces, and investigate structure-property relationships within chemical spaces. With an emphasis on drug discovery applications, we evaluate the open-source databases BIOFACQUIM and PeruNPDB as proof of concept.

Recombinant proteins as promising antigens applied to the immunodiagnosis of Chagas disease: a scoping review.

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is an important public health problem, occurring mainly in Latin America. The disease has a major social and economical effect, negatively impacting the life of the infected individuals, and bringing great costs to public health. An early and accurate diagnosis is essential for administration of early treatment. In addition, prognostic tests may aid disease management, decreasing hospitalization costs. However, the serological diagnostic scenario for CD still faces several challenges, making the development of new diagnostic kits a pressing matter. Facing this scenario, several researchers have expanded efforts in developing and testing new antigens, such as recombinant proteins and recombinant multiepitope proteins, with promising results. These recombinant antigens offer several advantages, such as improved sensitivity and specificity, in addition to facilitated scaling. Also, it has been possible to observe a rising number of studies using ELISA and point-of-care platforms, employing these antigens in the past few years. Among them, recombinant proteins were the most applied antigens, demonstrating great capacity to discriminate between positive and negative samples. Although fewer in number, recombinant multiepitope proteins also demonstrated an improved diagnostic performance. Indeed, a great number of studies employing these antigens showed sensitivity and specificity values above 90%, greatly impacting diagnostic accuracy. Nevertheless, despite the good results found, it is still possible to observe some bottlenecks in the development of new antigens, such as the scarcity of tests with sera from the acute phase and the variability of results in different geographic areas. In this sense, aiming to contribute to control and health programs, the continuous search for a more accurate serological diagnosis is essential, both for the acute and chronic phases of the disease.

A Mini-Review of Diagnostic Methods for the Antigen and Antibody Detection of Rocky Mountain and Brazilian Spotted Fever.

Rocky Mountain or Brazilian spotted fever, caused by Rickettsia rickettsii, is a fulminant, seasonal, and neglected disease that occurs in focal points of North America and South America. Its rapid detection is essential for the better prognosis and survival rate of infected individuals. However, disease diagnosis still faces challenges as the accuracy of many of the available laboratory tests fluctuates. This review aimed to analyze methods for antibody or antigen detection, their gaps, and their evolution over time. A search was conducted to find all studies in the Pubmed database that described the antibody or antigen detection of R. rickettsii infections. Initially, a total of 403 articles were screened. Of these articles, only 17 fulfilled the pre-established inclusion criteria and were selected. Among the different methods applied, the IFA technique was the one most frequently found in the studies. However, it presented varied results such as a low specificity when using the indirect method. Other techniques, such as ELISA and immunohistochemistry, were also found, although in smaller numbers and with their own limitations. Although some studies showed promising results, there is a pressing need to find new techniques to develop a rapid and effective diagnosis of R. rickettssi infection.

Global Distribution of Canine Visceral Leishmaniasis and the Role of the Dog in the Epidemiology of the Disease.

Visceral leishmaniasis is a disease caused by protozoa of the species Leishmania (Leishmania) infantum (syn = Leishmania chagasi) and Leishmania (Leishmania) donovani, which are transmitted by hematophagous insects of the genera Lutzomyia and Phlebotomus. The domestic dog (Canis familiaris) is considered the main urban reservoir of the parasite due to the high parasite load on its skin, serving as a source of infection for sandfly vectors and, consequently, perpetuating the disease in the urban environment. Some factors are considered important in the perpetuation and spread of canine visceral leishmaniasis (CVL) in urban areas, such as stray dogs, with their errant behavior, and houses that have backyards with trees, shade, and organic materials, creating an attractive environment for sandfly vectors. CVL is found in approximately 50 countries, with the number of infected dogs reaching millions. However, due to the difficulty of controlling and diagnosing the disease, the number of infected animals could be even greater. In the four continents endemic for CVL, there are reports of disease expansion in endemic countries such as Brazil, Italy, Morocco, and Tunisia, as well as in areas where CVL is not endemic, for example, Uruguay. Socio-environmental factors, such as migration, drought, deforestation, and global warming, have been pointed out as reasons for the expansion into areas where it had been absent. Thus, the objective of this review is to address (i) the distribution of CVL in endemic areas, (ii) the role of the dog in the visceral leishmaniasis epidemiology and the factors that influence dog infection and the spread of the disease, and (iii) the challenges faced in the control of CVL.

Targeting Leishmania infantum Mannosyl-oligosaccharide glucosidase with natural products: potential pH-dependent inhibition explored through computer-aided drug design.

Visceral Leishmaniasis (VL) is a serious public health issue, documented in more than ninety countries, where an estimated 500,000 new cases emerge each year. Regardless of novel methodologies, advancements, and experimental interventions, therapeutic limitations, and drug resistance are still challenging. For this reason, based on previous research, we screened natural products (NP) from Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB), Mexican Compound Database of Natural Products (BIOFACQUIM), and Peruvian Natural Products Database (PeruNPDB) databases, in addition to structural analogs of Miglitol and Acarbose, which have been suggested as treatments for VL and have shown encouraging action against parasite's N-glycan biosynthesis. Using computer-aided drug design (CADD) approaches, the potential inhibitory effect of these NP candidates was evaluated by inhibiting the Mannosyl-oligosaccharide Glucosidase Protein (MOGS) from Leishmania infantum, an enzyme essential for the protein glycosylation process, at various pH to mimic the parasite's changing environment. Also, computational analysis was used to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile, while molecular dynamic simulations were used to gather information on the interactions between these ligands and the protein target. Our findings indicated that Ocotillone and Subsessiline have potential antileishmanial effects at pH 5 and 7, respectively, due to their high binding affinity to MOGS and interactions in the active center. Furthermore, these compounds were non-toxic and had the potential to be administered orally. This research indicates the promising anti-leishmanial activity of Ocotillone and Subsessiline, suggesting further validation through in vitro and in vivo experiments.

Recombinant multiepitope proteins expressed in Escherichia coli cells and their potential for immunodiagnosis.

Recombinant multiepitope proteins (RMPs) are a promising alternative for application in diagnostic tests and, given their wide application in the most diverse diseases, this review article aims to survey the use of these antigens for diagnosis, as well as discuss the main points surrounding these antigens. RMPs usually consisting of linear, immunodominant, and phylogenetically conserved epitopes, has been applied in the experimental diagnosis of various human and animal diseases, such as leishmaniasis, brucellosis, cysticercosis, Chagas disease, hepatitis, leptospirosis, leprosy, filariasis, schistosomiasis, dengue, and COVID-19. The synthetic genes for these epitopes are joined to code a single RMP, either with spacers or fused, with different biochemical properties. The epitopes' high density within the RMPs contributes to a high degree of sensitivity and specificity. The RMPs can also sidestep the need for multiple peptide synthesis or multiple recombinant proteins, reducing costs and enhancing the standardization conditions for immunoassays. Methods such as bioinformatics and circular dichroism have been widely applied in the development of new RMPs, helping to guide their construction and better understand their structure. Several RMPs have been expressed, mainly using the Escherichia coli expression system, highlighting the importance of these cells in the biotechnological field. In fact, technological advances in this area, offering a wide range of different strains to be used, make these cells the most widely used expression platform. RMPs have been experimentally used to diagnose a broad range of illnesses in the laboratory, suggesting they could also be useful for accurate diagnoses commercially. On this point, the RMP method offers a tempting substitute for the production of promising antigens used to assemble commercial diagnostic kits.

The use of peptides for immunodiagnosis of human Chagas disease.

Chagas disease, caused by the protozoa Trypanosoma cruzi, continues to be a serious public health problem in Latin America, worsened by the limitations in its detection. Given the importance of developing new diagnostic methods for this disease, the present review aimed to verify the number of publications dedicated to research on peptides that demonstrate their usefulness in serodiagnosis. To this end, a bibliographic survey was conducted on the PubMed platform using the keyword "peptide" or "epitope" combined with "Chagas disease" or "Trypanosoma cruzi"; "diagno*" or "serodiagnosis" or "immunodiagnosis", without period restriction. An increasing number of publications on studies employing peptides in ELISA and rapid tests assays was verified, which confirms the expansion of research in this field. It is possible to observe that many of the peptides tested so far originate from proteins widely used in the diagnosis of Chagas, and many of them are part of commercial tests developed. In this sense, as expected, promising results were obtained for several peptides when tested in ELISA, as many of them exhibited sensitivity and specificity values above 90%. Furthermore, some peptides have been tested in several studies, confirming their diagnostic potential. Despite the promising results observed, it is possible to emphasize the need for extensive testing of peptides, using different serological panels, in order to confirm their potential. The importance of producing an effective assay capable of detecting the clinical stages of the disease, as well as new immunogenic antigens that enable new serological diagnostic tools for Chagas disease, is evident.

Immunotherapy Combining Mimotopes Selected by Phage Display Plus Amphotericin B Is Effective for Treatment Against Visceral Leishmaniasis.

The treatment for visceral leishmaniasis (VL) causes toxicity in patients, entails high cost and/or leads to the emergence of resistant strains. No human vaccine exists, and diagnosis presents problems related to the sensitivity or specificity of the tests. Here, we tested two phage clones, B1 and D11, which were shown to be protective against Leishmania infantum infection in a murine model as immunotherapeutics to treat mice infected with this parasite species. The phages were used alone or with amphotericin B (AmpB), while other mice received saline, AmpB, a wild-type phage (WTP) or WTP/AmpB. Results showed that the B1/AmpB and D11/AmpB combinations induced polarised Th1-type cellular and humoral responses, which were primed by high levels of parasite-specific IFN-γ, IL-12, TNF-α, nitrite and IgG2a antibodies, which reflected in significant reductions in the parasite load in distinct organs of the animals when analyses were performed 1 and 30 days after the treatments. Reduced organic toxicity was also found in these animals, as compared with the controls. In conclusion, preliminary data suggest the potential of the B1/AmpB and D11/AmpB combinations as immunotherapeutics against L. infantum infection.

A Review on the use of Synthetic and Recombinant Antigens for the Immunodiagnosis of Tegumentary Leishmaniasis.

Improving the diagnostic technology used to detect tegumentary leishmaniasis (TL) is essential in view of it being a widespread, often neglected tropical disease, with cases reported from the Southern United States to Northern Argentina. Recombinant proteins, recombinant multiepitope proteins, and synthetic peptides have been extensively researched and used in disease diagnosis. One of the benefits of applying these antigens is a measurable increase in sensitivity and specificity, which improves test accuracy. The present review aims to describe the use of these antigens and their diagnostic effectiveness. With that in mind, a bibliographic survey was conducted on the PudMed platform using the search terms "tegumentary leishmaniasis" AND "diagno", revealing that recombinant proteins have been described and evaluated for their value in TL diagnosis since the 1990s. However, there was a spike in the number of publications using all of the antigens between 2013 and 2022, confirming an expansion in research efforts to improve diagnosis. Moreover, all of the studies involving different antigens had promising results, including improved sensitivity and specificity. These data recognize the importance of doing research with new technologies focused on developing quick, more effective diagnostic kits as early diagnosis facilitates treatment.

Sarcocystis spp. of New and Old World Camelids: Ancient Origin, Present Challenges.

Sarcocystis spp. are coccidian protozoans belonging to the Apicomplexa phylum. As with other members of this phylum, they are obligate intracellular parasites with complex cellular machinery for the invasion of host cells. Sarcocystis spp. display dixenous life cycles, involving a predator and a prey as definitive and intermediate hosts, respectively. Specifically, these parasites develop sarcocysts in the tissues of their intermediate hosts, ranging in size from microscopic to visible to the naked eye, depending on the species. When definitive hosts consume sarcocysts, infective forms are produced in the digestive system and discharged into the environment via feces. Consumption of oocyst-contaminated water and pasture by the intermediate host completes the parasitic cycle. More than 200 Sarcocystis spp. have been described to infect wildlife, domestic animals, and humans, some of which are of economic or public health importance. Interestingly, Old World camelids (dromedary, domestic Bactrian camel, and wild Bactrian camel) and New World or South American camelids (llama, alpaca, guanaco, and vicuña) can each be infected by two different Sarcocystis spp: Old World camelids by S. cameli (producing micro- and macroscopic cysts) and S. ippeni (microscopic cysts); and South American camelids by S. aucheniae (macroscopic cysts) and S. masoni (microscopic cysts). Large numbers of Old and New World camelids are bred for meat production, but the finding of macroscopic sarcocysts in carcasses significantly hampers meat commercialization. This review tries to compile the information that is currently accessible regarding the biology, epidemiology, phylogeny, and diagnosis of Sarcocystis spp. that infect Old and New World camelids. In addition, knowledge gaps will be identified to encourage research that will lead to the control of these parasites.

Targeting with Structural Analogs of Natural Products the Purine Salvage Pathway in Leishmania (Leishmania) infantum by Computer-Aided Drug-Design Approaches.

Visceral Leishmaniasis (VL) has a high death rate, with 500,000 new cases and 50,000 deaths occurring annually. Despite the development of novel strategies and technologies, there is no adequate treatment for the disease. Therefore, the purpose of this study is to find structural analogs of natural products as potential novel drugs to treat VL. We selected structural analogs from natural products that have shown antileishmanial activities, and that may impede the purine salvage pathway using computer-aided drug-design (CADD) approaches. For these, we started with the vastly studied target in the pathway, the adenine phosphoribosyl transferase (APRT) protein, which alone is non-essential for the survival of the parasite. Keeping this in mind, we search for a substance that can bind to multiple targets throughout the pathway. Computational techniques were used to study the purine salvage pathway from Leishmania infantum, and molecular dynamic simulations were used to gather information on the interactions between ligands and proteins. Because of its low homology to human proteins and its essential role in the purine salvage pathway proteins network interaction, the findings further highlight the significance of adenylosuccinate lyase protein (ADL) as a therapeutic target. An analog of the alkaloid Skimmianine, N,N-diethyl-4-methoxy-1-benzofuran-6-carboxamide, demonstrated a good binding affinity to APRT and ADL targets, no expected toxicity, and potential for oral route administration. This study indicates that the compound may have antileishmanial activity, which was granted in vitro and in vivo experiments to settle this finding in the future.

Transmission-Blocking Vaccines for Canine Visceral Leishmaniasis: New Progress and Yet New Challenges.

Dogs with visceral leishmaniasis play a key role in the transmission cycle of Leishmania infantum to humans in the urban environment. There is a consensus regarding the importance of developing a vaccine to control this disease. Despite many efforts to develop a protective vaccine against CVL, the ones currently available, Leish-tec® and LetiFend®, have limited effectiveness. This is due, in part, to the complexity of the immune response of the naturally infected dogs against the parasite and the complexity of the parasite transmission cycle. Thus, strategies, such as the development of a transmission-blocking vaccines (TBVs) already being applied to other vector-borne diseases like malaria and dengue, would be an attractive alternative to control leishmaniasis. TBVs induce the production of antibodies in the vertebrate host, which can inhibit parasite development in the vector and/or interfere with aspects of vector biology, leading to an interruption of parasite transmission. To date, there are few TBV studies for CVL and other leishmaniasis forms. However, the few studies that exist show promising results, thus justifying the further development of this approach.

Advances in Non-Chemical Tools to Control Poultry Hematophagous Mites.

The blood-sucking mites Dermanyssus gallinae ("red mite"), Ornithonyssus sylviarum ("northern fowl mite"), and Ornithonyssus bursa ("tropical fowl mite") stand out for causing infestations in commercial poultry farms worldwide, resulting in significant economic damage for producers. In addition to changes in production systems that include new concerns for animal welfare, global climate change in recent years has become a major challenge in the spread of ectoparasites around the world. This review includes information regarding the main form of controlling poultry mites through the use of commercially available chemicals. In addition, non-chemical measures against blood-sucking mites were discussed such as extracts and oils from plants and seeds, entomopathogenic fungi, semiochemicals, powder such as diatomaceous earth and silica-based products, and vaccine candidates. The control of poultry mites using chemical methods that are currently used to control or eliminate them are proving to be less effective as mites develop resistance. In contrast, the products based on plant oils and extracts, powders of plant origin, fungi, and new antigens aimed at developing transmission-blocking vaccines against poultry mites provide some encouraging options for the rational control of these ectoparasites.

Computer-aided drug design approaches applied to screen natural product's structural analogs targeting arginase in Leishmania spp.

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics-generalized Born surface area (MM-GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.

Molecular methods for diagnosis of monkeypox: A mini-review.

BACKGROUND: Monkeypox is a global public health issue caused by the monkeypox virus (MPXV). As of October 28, 2022, a total of 77,115 laboratory-confirmed cases and 3,610 probable cases, including 36 deaths, were reported, with 9,070 cases reported in Brazil, the second most affected country. The need to develop national technologies for the rapid diagnosis of emerging diseases for mass testing of the population is evident, as observed in the SARS-CoV-2 pandemic. OBJECTIVE: With that in mind, this article provides an overview of current methods, techniques, and their applications in the molecular detection of monkeypox, focusing the search on real-time polymerase chain reaction (qPCR), polymerase chain reaction (PCR), and polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA). METHODS: The relevant documents or papers covered in this study were selected by a search in international bibliographic databases. The search terms used in the databases were aimed at summarizing existing knowledge on molecular diagnostic methods, such as monkeypox; MPX, MPXV, qPCR, PCR, PCR-ELISA, diagnosis and detection searched separately or together using the Boolean operator "AND" either in the title or abstract. The searches took place in September 2022, and the corresponding articles were selected between 2012 and 2022. RESULTS: We found 256 documents in total and twelve studies addressing the molecular diagnosis of monkeypox were classified as possible sources for this review. CONCLUSION: It is evident there is a pressing need to develop national technologies for rapid diagnosis of emerging diseases for mass testing of the population. It is also extremely important to have national detection kits with greater diagnostic capacity to assist in developing effective public policies in countries affected by this disease.

A mini-review on ELISA-Based Diagnosis of Schistosomiasis.

BACKGROUND: schistosomiasis is a neglected tropical parasitic disease caused by trematode worms of the genus schistosoma, which affects approximately 240 million people worldwide. the diagnosis of the disease can be performed by parasitological, molecular, and/or immunological methods, however, the development of new diagnostic methods still essential to guide policy decisions, monitor disease trends and assess the effectiveness of interventions. OBJECTIVE: in this sense, the current work summarizes the findings of a systematic review regarding antigens applied in the enzyme-linked immunosorbent assay test, which were patented and published over the last ten years. METHODS: the literature search strategy used medical subject heading (mesh) terms to define as descriptors. "schistosoma mansoni" was used in arrangement with the descriptors "immunoassay", "enzyme-linked immunosorbent assay", "elisa", and "antigens", using the "and" connector. the patent search was done using keywords, including diagnosis and schistosoma or schistosomiasis or schistosome. several databases were employed for the patent search, such as intellectual property national institute; european patent office; the united states patent and trademark office; patent scope, and google patents. RESULTS: forty-one articles were retrieved, of which only five met the eligibility criteria. seventeen patents were taken from the databases, and a brief description of the most relevant inventions is given here. CONCLUSION: schistosomiasis is considered the most important helminthic disease in worldwide. therefore, it is important to of searching for and develops diagnostic methods based on serology to reduce morbidity and mortality caused by the disease.

A Systematic Review and Meta-Analysis Comparing the Diagnostic Accuracy Tests of COVID-19.

In this paper, we present a systematic review and meta-analysis that aims to evaluate the reliability of coronavirus disease diagnostic tests in 2019 (COVID-19). This article seeks to describe the scientific discoveries made because of diagnostic tests conducted in recent years during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Between 2020 and 2021, searches for published papers on the COVID-19 diagnostic were made in the PubMed database. Ninety-nine scientific articles that satisfied the requirements were analyzed and included in the meta-analysis, and the specificity and sensitivity of the diagnostic accuracy were assessed. When compared to serological tests such as the enzyme-linked immunosorbent assay (ELISA), chemiluminescence immunoassay (CLIA), lateral flow immunoassay (LFIA), and chemiluminescent microparticle immunoassay (CMIA), molecular tests such as reverse transcription polymerase chain reaction (RT-PCR), reverse transcription loop-mediated isothermal amplification (RT-LAMP), and clustered regularly interspaced short palindromic repeats (CRISPR) performed better in terms of sensitivity and specificity. Additionally, the area under the curve restricted to the false-positive rates (AUCFPR) of 0.984 obtained by the antiviral neutralization bioassay (ANB) diagnostic test revealed significant potential for the identification of COVID-19. It has been established that the various diagnostic tests have been effectively adapted for the detection of SARS-CoV-2; nevertheless, their performance still must be enhanced to contain potential COVID-19 outbreaks, which will also help contain potential infectious agent outbreaks in the future.

PeruNPDB: the Peruvian Natural Products Database for in silico drug screening.

Since the number of drugs based on natural products (NPs) represents a large source of novel pharmacological entities, NPs have acquired significance in drug discovery. Peru is considered a megadiverse country with many endemic species of plants, terrestrial, and marine animals, and microorganisms. NPs databases have a major impact on drug discovery development. For this reason, several countries such as Mexico, Brazil, India, and China have initiatives to assemble and maintain NPs databases that are representative of their diversity and ethnopharmacological usage. We describe the assembly, curation, and chemoinformatic evaluation of the content and coverage in chemical space, as well as the physicochemical attributes and chemical diversity of the initial version of the Peruvian Natural Products Database (PeruNPDB), which contains 280 natural products. Access to PeruNPDB is available for free ( https://perunpdb.com.pe/ ). The PeruNPDB's collection is intended to be used in a variety of tasks, such as virtual screening campaigns against various disease targets or biological endpoints. This emphasizes the significance of biodiversity protection both directly and indirectly on human health.

A Mini-review on Potentials Proteins/Peptides Applied for Serodiagnosis of Human Monkeypox Infection and Future Trends.

Monkeypox is a zoonosis that re-emerged in 2022, generating cases in non-endemic countries for the disease and creating a public health issue. The rapid increase in the number of cases kindles a need for quick, inexpensive diagnostic tests for the epidemiological control of the disease. The high cost of molecular tests can make this control more difficult to access in poorer regions, with immunological tests being a more viable option. In this mini-review, a search was conducted in the main databases for peptide and protein options that could be used in the development of serological diagnostic tests. Nine viable registres were found, and seven were selected (two patents and five studies). The main studies used the B21R peptide sequence as it is a high immunogenic epitope. In addition, studies on the improvement of these sequences were also found to avoid cross-reactions against other viruses of the same family, proposing a rational approach using multiepitope recombinant proteins. These approaches demonstrated high sensitivity and specificity values and are seen as viable options for developing new tests. New effective serological testing options, when combined with awareness, disease surveillance, early diagnosis, and rapid communication, form a set of key strategies used by health systems to control the spread of the monkeypox virus.

Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family.

Evidence suggests that there may be racial differences in risk factors associated with the development of Alzheimer's disease and related dementia (ADRD). We used whole-genome sequencing analysis and identified a novel combination of three pathogenic variants in the heterozygous state (UNC93A: rs7739897 and WDR27: rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of affected individuals but absent in healthy members of the family. In silico and in vitro studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may affect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our findings have thus identified a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background.