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Bacterial vaginosis and inflammatory response showed association with severity of cervical neoplasia in HPV-positive women
(2016) Castro Sobrinho, Juçara Maria de; Santos, Silvia Helena Rabelo dos; Alves, Rosane Ribeiro Figueiredo; Derchain, Sophie Françoise Mauricette; Sarian, Luis Otávio Zanatta; Moraes, Denise da Rocha Pitta Lima de; Campos, Elisabete A.; Zeferino, Luiz Carlos
Vaginal infections may affect susceptibility to and clearance of human papillomavirus (HPV) infection and chronic inflammation has been linked to carcinogenesis. This study aimed to evaluate the association between bacterial vaginosis (BV) and inflammatory response (IR) with the severity of cervical neoplasia in HPV-infected women. HPV DNA was amplified using PGMY09/11 primers and genotyping was performed using a reverse line blot hybridization assay in 211 cervical samples from women submitted to excision of the transformation zone. The bacterial flora was assessed in Papanicolaou stained smears, and positivity for BV was defined as ≥20% of clue cells. Present inflammatory response was defined as ≥30 neutrophils per field at 1000× magnification. Age higher than 29 years (OR:1.91 95% CI 1.06–3.45), infections by the types 16 and/or 18 (OR:1.92 95% CI 1.06–3.47), single or multiple infections associated with types 16 and/or 18 (OR: 1.92 CI 95% 1.06–3.47), BV (OR: 3.54 95% CI 1.62–7.73) and IR (OR: 6.33 95% CI 3.06–13.07) were associated with severity of cervical neoplasia (CIN 2 or worse diagnoses), while not smoking showed a protective effect (OR: 0.51 95% CI 0.26–0.98). After controlling for confounding factors, BV(OR: 3.90 95% CI 1.64–9.29) and IR (OR: 6.43 95% CI 2.92–14.15) maintained their association with the severity of cervical neoplasia. Bacterial vaginosis and inflammatory response were independently associated with severity of cervical neoplasia in HPV-positive women, which seems to suggest that the microenvironment would relate to the natural history of cervical neoplasia.
Human papillomavirus in oral cavity and oropharynx carcinomas in the central region of Brazil
(2017) Petito, Guilherme; Carneiro, Megmar Aparecida dos Santos; Santos, Silvia Helena Rabelo dos; Silva, Antonio Márcio Teodoro Cordeiro; Alencar, Rita de Cássia Gonçalves de; Gontijo, Antonio Paulo Machado; Saddi, Vera Aparecida
Introduction: Molecular studies about carcinomas of the oral cavity and oropharynx demon strate the presence of human papilomavirus genome in these tumors, reinforcing the participation of human papilomavirus in oral carcinogenesis. Objectives: This study aimed to determine the prevalence of human papilomavirus and geno type distribution of HPV16 and HPV18 in oral cavity and oropharynx carcinomas, as well as their association with clinical characteristics of the tumors. Methods: This is a retrospective study, with clinical data collected from 82 patients. Human papilomavirus detection was conducted on specimens of oral cavity and oropharynx carcinomas included in paraffin blocks. Patients were assisted in a cancer reference center, in the central region of Brazil, between 2005 and 2007. Polymerase chain reaction was used for the detection and genotyping of human papilomavirus. Results: Among the patients evaluated, 78% were male. The average age of the group was about 58 years. Risk factors, such as smoking (78%) and alcohol consumption (70.8%) were recorded for the group. HPV DNA was detected in 21 cases (25.6%; 95% confidence interval 16.9---36.6) of which 33.3% were HPV16 and 14.3% were HPV18. The presence of lymph node metastases and registered deaths were less frequent in human papilomavirus positive tumors, suggesting a better prognosis for these cases; however, the differences between the groups were not statistically significant.
Strong SOD2 expression and HPV-16/18 positivity are independent events in cervical cancer
(2018) Santos, Silvia Helena Rabelo dos; Termini, Lara; Pierulivo, Enrique Mario Boccardo; Derchain, Sophie Françoise Mauricette; Longatto Filho, Adhemar; Andreoli, Maria Antonieta Avilla; Costa, Maria Cecília; Nunes, Rafaella Almeida Lima; Andrade, Liliana Aparecida Lucci de Angelo; Villa, Luisa Lina
Human papillomavirus and anal cancer: prevalence, genotype distribution, and prognosis aspects from midwestern region of Brazil
(2019) Libera, Larisse Silva Dalla; Carvalho, Keila Patrícia Almeida de; Ramos, Jessica Enocencio Porto; Cabral, Lázara Alyne Oliveira; Alencar, Rita de Cássia Gonçalves de; Villa, Luísa Lina; Alves, Rosane Ribeiro Figueiredo; Santos, Silvia Helena Rabelo dos; Carneiro, Megmar Aparecida dos Santos; Saddi, Vera Aparecida
d. Approximately 90% of all anal cancers are associated with human papillomavirus (HPV), especially high-risk genotypes such as HPVs 16 and 18. Objective. To investigate the clinical and prognostic aspects of anal cancers associated with the presence, as well as the genotypic distribution of human papillomavirus (HPV). Methods. A retrospective study carried out over a 10-year period, using clinical and molecular data, with PCR analysis and reverse hybridization (INNO LIPA kit), in anal cancers. ,e data analysis was done using descriptive univariate statistics, and the survival curves were made using the Kaplan–Meier and log-rank methods. Results. Of the 81 formalin-fixed and paraffin-embedded specimens, HPV prevalence was 69% and was significantly higher in squamous cell carcinomas (SCC) than in other anal tumors (p � 0.0001). Female patients had a higher prevalence of HPV (p � 0.01). Multiple infections were detected in 14.3% of cases. ,e most prevalent genotypes were HPVs 16, 33, and 18. ,e overall survival at 60 months was 44.3%, and the prognostic factors included gender (p � 0.008) with greater survival for men (52.9%) in comparison to women (29.6%), histological type (p � 0.01), SCC (54.4%), adenocarcinomas (37.5%), other carcinomas (14.2%), and the presence of distant metastasis (p � 0.01). Survival was not influenced by the presence of HPV (p � 0.54). Conclusions. ,e association of HPV to anal cancer was found in this study, especially in SCC. However, the presence of HPV did not influence the prognosis of patients with anal cancer.
Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population
(2019) Silveira, Caio Raony Farina; Manzine, Marcella Cipelli Carolina; Santos, Silvia Helena Rabelo dos; Zeferino, Luiz Carlos; Rodríguez Rodríguez, Gretel; Assis, Josiane Betim de; Herbster, Suellen da Silva Gomes; Bernadinelli, Isabel; Laginha, Fábio Martins
Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, con tinues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identi fied α-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainso nine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed α-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phe notype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo, SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contrib utes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth.
Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGFA in cervical cancer patient survival: a competing risk analysis
(2016) Martins, Jordana Maria Azevedo; Santos, Silvia Helena Rabelo dos; Westin, Maria Cristina do Amaral; Zeferino, Luiz Carlos
Background Human papillomavirus and Chlamydia trachomatis share the same route of sexual transmission and possess similar risk factors, indicating that coinfection may act synergistically in the induction of epithelial cell abnormalities. Objective This study aimed to determine the prevalence of human papillomavirus and Chlamydia trachomatis in adolescents and young women and identify factors associated with coinfection. Study Design This cross-sectional study included 276 female participants, aged 15–24 years, who were sexually active. Interviews were conducted and cervical specimens were collected for cervical smears and molecular tests. All cervical specimens were tested for 27 human papillomavirus genotypes by polymerase chain reaction amplification and hybridization to a human papillomavirus linear array. Detection of Chlamydia trachomatis was performed by polymerase chain reaction using primers directed to the region encoding the cryptic plasmid. Bivariate and multivariate analyses were performed to evaluate the factors associated with coinfection with human papillomavirus and Chlamydia trachomatis. The odds ratio, the adjusted odds ratio, and the 95% confidence interval were calculated. Results The prevalence of infection by Chlamydia trachomatis and human papillomavirus was 9.1% (95% confidence interval, 5.61–12.4) and 47.1% (95% confidence interval, 41.0–53.2), respectively. The prevalence of coinfection with human papillomavirus and Chlamydia trachomatis was 5.8% (95% confidence interval, 3.3–9.2); coinfection with 1 human papillomavirus type was 3.3% (95% confidence interval, 1.5–6.1) and with multiple types was 2.5% (95% confidence interval, 1.0–5.2). The prevalence of cytological abnormalities was 12.3% (95% confidence interval, 8.6–16.79). Human papillomavirus infections of high oncogenic risk were more prevalent (85.4%). Factors independently associated with coinfection of human papillomavirus/Chlamydia trachomatis obtained by multivariate analysis were the initiation of sexual activity under 16 years of age with an an odds ratio of 4.9 (95% confidence interval, 1.0–23.63; P = .05) and cytological abnormalities with an odds ratio of 10.7 (95% confidence interval, 1.9–59.5; P = .01), which indicates there is risk for the detection of cytological abnormalities in adolescents and young women coinfected with human papillomavirus/Chlamydia trachomatis. Conclusion The prevalence of coinfection among our study population was of a magnitude that warrants attention by public health services. Adolescents and young women should be monitored for Chlamydia trachomatis infection and vaccinated against human papillomavirus. The association between cytological abnormalities and coinfection with human papillomavirus and Chlamydia trachomatis indicates the potential synergistic role of these infections in carcinogenesis of the cervix.
Three Prime Repair Exonuclease 1 (TREX1) expression correlates with cervical cancer cells growth in vitro and disease progression in vivo
(2019) Abjaude, Bruna Prati Walason da Silva; Morale, Lara Termini Mirian Galliote; Herbster, Suellen da Silva Gomes; Longatto Filho, Adhemar; Nunes, Rafaella Almeida Lima; Córdoba Camacho, Lizeth Carolina; Santos, Silvia Helena Rabelo dos; Zeferino, Luiz Carlos; Aguayo, Francisco; Boccardo Pierulivo, Enrique Mario
Alterations in specifc DNA damage repair mechanisms in the presence of human papillomavirus (HPV) infection have been described in diferent experimental models. However, the global efect of HPV on the expression of genes involved in these pathways has not been analyzed in detail. In the present study, we compared the expression profle of 135 genes involved in DNA damage repair among primary human keratinocytes (PHK), HPV-positive (SiHa and HeLa) and HPV-negative (C33A) cervical cancer derived cell lines. We identifed 9 genes which expression pattern distinguishes HPV-positive tumor cell lines from C33A. Moreover, we observed that Three Prime Repair Exonuclease 1 (TREX1) expression is upregulated exclusively in HPV-transformed cell lines and PHK expressing HPV16 E6 and E7 oncogenes. We demonstrated that TREX1 silencing greatly afects tumor cells clonogenic and anchorage independent growth potential. We showed that this efect is associated with p53 upregulation, accumulation of subG1 cells, and requires the expression of E7 from high-risk HPV types. Finally, we observed an increase in TREX1 levels in precancerous lesions, squamous carcinomas and adenocarcinomas clinical samples. Altogether, our results indicate that TREX1 upregulation is important for cervical tumor cells growth and may contribute with tumor establishment and progression.
Prevalence and factors associated with coinfection of human papillomavirus and Chlamydia trachomatis in adolescents and young women
(2016) Nonato, Dejan Rodrigues; Alves, Rosane Ribeiro Figueiredo; Ribeiro, Andrea Alves; Saddi, Vera Aparecida; Segati, Kelly Deyse; Carvalho, Keila Patrícia Almeida de; Lima, Yanna Andressa Ramos de; D'Alessandro, Walmirton Bezerra; Santos, Silvia Helena Rabelo dos
Background Human papillomavirus and Chlamydia trachomatis share the same route of sexual transmission and possess similar risk factors, indicating that coinfection may act synergistically in the induction of epithelial cell abnormalities. Objective This study aimed to determine the prevalence of human papillomavirus and Chlamydia trachomatis in adolescents and young women and identify factors associated with coinfection. Study Design This cross-sectional study included 276 female participants, aged 15–24 years, who were sexually active. Interviews were conducted and cervical specimens were collected for cervical smears and molecular tests. All cervical specimens were tested for 27 human papillomavirus genotypes by polymerase chain reaction amplification and hybridization to a human papillomavirus linear array. Detection of Chlamydia trachomatis was performed by polymerase chain reaction using primers directed to the region encoding the cryptic plasmid. Bivariate and multivariate analyses were performed to evaluate the factors associated with coinfection with human papillomavirus and Chlamydia trachomatis. The odds ratio, the adjusted odds ratio, and the 95% confidence interval were calculated. Results The prevalence of infection by Chlamydia trachomatis and human papillomavirus was 9.1% (95% confidence interval, 5.61–12.4) and 47.1% (95% confidence interval, 41.0–53.2), respectively. The prevalence of coinfection with human papillomavirus and Chlamydia trachomatis was 5.8% (95% confidence interval, 3.3–9.2); coinfection with 1 human papillomavirus type was 3.3% (95% confidence interval, 1.5–6.1) and with multiple types was 2.5% (95% confidence interval, 1.0–5.2). The prevalence of cytological abnormalities was 12.3% (95% confidence interval, 8.6–16.79). Human papillomavirus infections of high oncogenic risk were more prevalent (85.4%). Factors independently associated with coinfection of human papillomavirus/Chlamydia trachomatis obtained by multivariate analysis were the initiation of sexual activity under 16 years of age with an an odds ratio of 4.9 (95% confidence interval, 1.0–23.63; P = .05) and cytological abnormalities with an odds ratio of 10.7 (95% confidence interval, 1.9–59.5; P = .01), which indicates there is risk for the detection of cytological abnormalities in adolescents and young women coinfected with human papillomavirus/Chlamydia trachomatis. Conclusion The prevalence of coinfection among our study population was of a magnitude that warrants attention by public health services. Adolescents and young women should be monitored for Chlamydia trachomatis infection and vaccinated against human papillomavirus. The association between cytological abnormalities and coinfection with human papillomavirus and Chlamydia trachomatis indicates the potential synergistic role of these infections in carcinogenesis of the cervix.
Internal quality control indicators in cervical cytopathology of a university laboratory
(2018) Cardoso Filho, Leonardo Izidório; Tavares, Suelene Brito do Nascimento; Batista, Maria de Lourdes Siqueira; Passos, Eva Nayssa dos; Araújo, N. L. A. S.; Martins, Jordana Maria Azevedo; Ribeiro, Andrea Alves; Santos, Silvia Helena Rabelo dos
Introduction To evaluate the internal quality control indicators and quality management programme in a university cytopathology laboratory. Methods All results of conventional cervical smears tests (taken from the SISCAN, the Brazilian cervical cancer screening system) of women aged ≥15 years at the time of Papanicolaou smear specimen collection during January 2007-December 2014 were included. The final results of the cytopathology were classified in accordance with the Bethesda System. The variables included in the database were the woman's name, date of birth, and age at the time of sampling (15-30, 31-40 and older than 40 years). Results In this period, 50 286 cytopathology examinations were carried out. Of these, 44 386 (91.34%) were negative for malignancy or unsatisfactory and 4209 (8.66%) presented epithelial abnormalities. The percentage of the tests consistent with atypical squamous cells (ASC) between satisfactory examinations was 4.12%; the percentage of tests compatible with ASC among abnormal examinations was 47.87%; the ASC/squamous intraepithelial lesion) ratio was 0.97 and the percentage of high-grade squamous intraepithelial lesion among satisfactory tests was 2.21%, and the 5-year retrospective review identified 4.97% of false-negative results. Conclusion All rates obtained were consistent over the years and within the recommended values by Federal Regulation of Brazil. This demonstrates the efficacy of our established internal quality monitoring and continuing education, reflecting the commitment of the team involved in the release of smear reports.
Bacterial vaginosis, representation of endocervical and/or metaplastic cells, and cytological abnormalities in different age groups: association study
(2020) Passos, Eva Nayssa do; Ribeiro, Andrea Alves; Tavares, Suelene Brito do Nascimento; Souza, Nadja Lindany Alves de; Batista, Maria de Lourdes Siqueira; Cardoso Filho, Leonardo Izidório; Aquino, Érika Carvalho de; Santos, Silvia Helena Rabelo dos
Background Studies have indicated that bacterial vaginosis (BV) might be a cofactor for the acquisition and persistence of high-risk papillomavirus, enabling the development of cytological abnormalities. The presence of endocervical and metaplastic cells makes the smear more adequate for the detection of these abnormalities once these cell types are representative of the transformation zone, a site of increased susceptibility to viral infection. Methods The purpose of this study was to evaluate the patterns of vaginal microbiota, the representation of endocervical and/or metaplastic cells, and the detection of cytological abnormalities in cervical smears from women 15 to 64 years old. Results from satisfactory cytological smears performed in a laboratory school from the Federal University of Goiás were analyzed. The degree of association between the categorical variables was evaluated by the χ2 test, Fisher's Exact test, and stratified analysis through the estimation of the prevalence ratio, with 95% confidence intervals and 5% statistical significance level (P < .05). Results The global prevalence of BV and cytological abnormalities was 22.02% and 8.21%, respectively. BV and the representation of endocervical and/or metaplastic cells were independently associated with the detection of high-grade cytological abnormalities in the cervical smears of women between 25 and 64 years old. Conclusions BV and representation of endocervical and/or metaplastic cells were independently associated with the detection of high-grade cytological abnormalities reinforcing the importance of specimen adequacy and microbiota in the cervical microenvironment.
QSAR-Driven design and discovery of novel compounds with antiplasmodial and transmission blocking activities
(2018) Lima, Marília Nunes do Nascimento; Melo Filho, Cleber Camilo do; Cassiano, Gustavo Capatti; Neves, Bruno Junior; Alves, Vinícius de Medeiros; Braga, Rodolpho de Campos; Cravo, Pedro Vitor Lemos; Muratov, Eugene; Paim, Juliana Calit; Bargieri, Daniel Youssef; Costa, Fabio Trindade Maranhão; Andrade, Carolina Horta
Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium, affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum (PfdUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei. We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as PfdUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual PfdUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.
Development of Web and mobile applications for chemical toxicity prediction
(2018) Alves, Vinícius de Medeiros; Braga, Rodolpho de Campos; Muratov, Eugene; Andrade, Carolina Horta
Computational tools are recognized to provide high-quality predictions for the assessment of chemical toxicity. In the recent years, mobile devices have become ubiquitous, allowing for the development of innovative and useful models implemented as chemical software applications. Here, we will briefly discuss this recent uptick in the development of web-based and mobile applications for chemical problems, focusing on best practices, development, usage and interpretation. As an example, we also describe two innovative apps (Pred-hERG and Pred-Skin) for chemical toxicity prediction developed in our laboratory. These applications are based on predictive quantitative structure-activity relationships (QSAR) models developed using the largest publicly available datasets of structurally diverse compounds. The developed tools ensure both highly accurate predictions and easy interpretation of the models, allowing users to discriminate potential toxicants and to purpose structural modifications to design safer chemicals.
Quimioinformática: uma introdução
(2018) Alves, Vinícius de Medeiros; Braga, Rodolpho de Campos; Muratova, Eugene; Andrade, Carolina Horta
Cheminformatics is an interdisciplinary field between chemistry and informatics, which has evolved considerably since its inception in the 1960s. Initially, the cheminformatics community dealt primarily with practical and technical aspects of chemical structure representation, manipulation, and processing, while modern research explores a new role: the exploration and interpretation of large chemical databases and the discovery of new compounds with desired activity and safety profiles. Despite the recent release of several hallmark reviews addressing methods and application of cheminformatics written in Portuguese, so far there are no scientific articles presenting cheminformatics research to the Brazilian scientific community yet. To address this gap, we aim to introduce the field of cheminformatics to both students and researchers in a simple and didactic way by narrating important historical facts and contextualizing information within the scope of various applications.
Perspectivas da química medicinal para o século XXI: desafios e oportunidades
(2018) Andrade, Carolina Horta; Kümmerle, Arthur Eugen; Guido, Rafael Victorio Carvalho
In the 21st century, medicinal chemists will face many challenges to improve the quality of life of populations. The challenges consist of emerging infectious (ex. bacterial, viral and parasite infections) and non-communicable diseases (ex. autoimmune, Alzheimer disease, Parkinson’s disease) that will require innovative technologies (ex. microfluidics, nanotechnology, biotechnology) to be fully understood and combated. In this work, we indicate trends, perspectives and opportunities related to drug discovery as well as highlight the tools and strategies that could be used in drug discovery of the 21st century
OpenZika: an IBM world community grid project to accelerate Zika virus drug discovery
(2016) Ekins, Sean; Perryman, Alexander Luke; Andrade, Carolina Horta
The Zika virus outbreak in the Americas has caused global concern. To help accelerate this fight against Zika, we launched the OpenZika project. OpenZika is an IBM World Community Grid Project that uses distributed computing on millions of computers and Android devices to run docking experiments, in order to dock tens of millions of drug-like compounds against crystal structures and homology models of Zika proteins (and other related flavivirus targets). This will enable the identification of new candidates that can then be tested in vitro, to advance the discovery and development of new antiviral drugs against the Zika virus. The docking data is being made openly accessible so that all members of the global research community can use it to further advance drug discovery studies against Zika and other related flaviviruses.
The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery
(2016) Neves, Bruno Junior; Dantas, Rafael Ferreira; Senger, Mário Roberto; Valente, Walter César Góes; Rezende Neto, João de Mello; Chaves, Willian Távora; Kamentsky, Lee; Carpenter, Anne; Silva Junior, Floriano Paes; Andrade, Carolina Horta
Recently, our in silico repositioning-chemogenomics approach predicted paroxetine (PAR), an antidepressant drug, as a inhibitor of Schistosoma mansoni serotonin transporters (SmSERTs), and consequently, a new anti-schistosomal candidate. With the aim of determining the anti-schistosomal activity of this drug, we initially used a spectrophotometric assay to determine activity against schistosomula worms. During this investigation, we verified that PAR showed a pronounced effect on schistosomula viability (IC50 = 2.5 μM) after 72 h of incubation. Then, we performed ex vivo studies with adult S. mansoni worms using a new automated image-based assay to accurately measure worm motility. As expected from the PAR's predicted mechanism of action, both male and female worms treated with low concentrations of PAR exhibited enhanced motility followed by reduction in motility as incubation time increased. PAR EC50 values for motility reduction in male and female worms were 5.1 μM and 9.9 μM after 24 h of exposure, respectively, and this effect was maintained until the end of the experiment (72 h). Lastly, homology modeling and docking studies with SmSERT-A and human SERT (hSERT) revealed insights into the chemical basis of PAR anti-schistosomal activity. These results provide crucial guidance for further studies to optimize PAR in terms of potency and selectivity.
A evolução da química medicinal no Brasil: avanços nos 40 anos da Sociedade Brasileira de Química
(2017) Amaral, Antonia Tavares do; Andrade, Carolina Horta; Kummerle, Arthur Eugen; Guido, Rafael Victorio Carvalho
MEDICINAL CHEMISTRY PROGRESS IN BRAZIL: ADVANCES IN THE 40 YEARS OF THE BRAZILIAN CHEMICAL SOCIETY. Medicinal Chemistry includes the invention, discovery, design, identification, and interpretation of the molecular mechanism of action of biologically active compounds. In addition to the discovery of bioactive molecules, Medicinal Chemistry investigates drug metabolism and the relationships between chemical structure and biological activity. The advances achieved in the 20th century have significantly contributed to the better understanding of pathophysiological processes as well as the development of new, safer and more effective drugs for many diseases. In this article, we review the evolution of Medicinal Chemistry in Brazil during the last 40 years and evaluate the impact of the Brazilian contributions in the international context. The analyzed data revealed that Medicinal Chemistry research in Brazil has increased exponentially in the last two decades, the research groups became more well-distributed across the Brazilian regions and our scientific contributions have significant impact in the main journals of the field. Therefore, aiming at evolving steadily and striving for excellence in drug discovery and development, we shall focus on national and international collaborations and investment in translational research, as well.
A diarylamine derived from anthranilic acid inhibits ZIKV replication
(2019) Silva, Suely da; Shimizu, Jacqueline Farinha; Oliveira, Débora Moraes; Assis, Leticia Ribeiro de; Oliva, Cíntia Bittar; Mottin, Melina; Sousa, Bruna Katiele de Paula; Mesquita, Nathalya Cristina de Moraes Roso; Regasini, Luis Octávio; Rahal, Paula; Andrade, Carolina Horta
Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms. In silico results predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigated in vitro and we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel.
Cheminformatics-driven discovery of polymeric micelle formulations for poorly soluble drugs
(2019) Alves, Vinícius de Medeiros; Hwang, Duhyeong; Muratov, Eugene; Sokolsky-Papkov, Marina; Varlamova, Ekaterina; Vinod, Natasha; Chaemin, Lim; Andrade, Carolina Horta; Tropsha, Alexander; Kabanov, Alexander V.
Many drug candidates fail therapeutic development because of poor aqueous solubility. We have conceived a computer-aided strategy to enable polymeric micelle-based delivery of poorly soluble drugs. We built models predicting both drug loading efficiency (LE) and loading capacity (LC) using novel descriptors of drug-polymer complexes. These models were employed for virtual screening of drug libraries, and eight drugs predicted to have either high LE and high LC or low LE and low LC were selected. Three putative positives, as well as three putative negative hits, were confirmed experimentally (implying 75% prediction accuracy). Fortuitously, simvastatin, a putative negative hit, was found to have the desired micelle solubility. Podophyllotoxin and simvastatin (LE of 95% and 87% and LC of 43% and 41%, respectively) were among the top five polymeric micelle-soluble compounds ever studied experimentally. The success of the strategy described herein suggests its broad utility for designing drug delivery systems.
QSAR-driven discovery of novel chemical scaffolds active against schistosoma mansoni
(2016) Melo Filho, Cleber Camilo; Dantas, Rafael Ferreira; Braga, Rodolpho de Campos; Neves, Bruno Junior; Senger, Mário Roberto; Valente, Walter César Góes; Rezende Neto, João de Mello; Chaves, Willian Távaro; Muratov, Eugene; Paveley, Ross; Andrade, Carolina Horta
Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure–activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents.

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