RESUMO
BACKGROUND: The recent Zika virus (ZIKAV) epidemics disclosed a major public health threat and a scientific and technological (S&T) challenge. The lessons learned from the S&T response of Latin America and the Caribbean (LAC) countries are critical to inform further research and guide scientific investments. The present study aimed to assess how new S&T knowledge produced and disseminated regionally can contribute to address global health challenges. METHODS: Scientometric and social network analysis methods were used to assess the LAC scientific contribution and potential technological development on ZIKAV up to December 2017. ZIKAV-related publications were retrieved from the Web of Science, Scopus, and PubMed databases. Regionally published articles were obtained from SciELO (Scientific Electronic Library Online) and LILACS (Literature in the Health Sciences in Latin America and the Caribbean) databases. Patent registries were retrieved using Orbit Intelligence and Derwent Innovation. Records from each database were individually downloaded, integrated, standardized and analyzed. RESULTS: We retrieved 5421 ZIKAV-related publications, revealing a sharp increase from 2015 onwards. LAC countries accounted for 20% of all publications and Brazil was among the top three most central countries in the global network for ZIKAV research. A total of 274 patent families backed up by experimental evidence were retrieved. Only 5% were filed by LAC assignees, all of them based in Brazil. The largest contribution of LAC research was on the clinical manifestations of the ZIKAV infection, along with vector control, which was also the main focus of patents. CONCLUSIONS: Our analysis offered a comprehensive overview of ZIKAV's research and development and showed that (i) LAC countries had a key role in generating and disseminating scientific knowledge on ZIKAV; (ii) LAC countries have expressively contributed to research on ZIKAV clinical manifestations; (iii) the Brazilian scientific community was potentially very effective in knowledge sharing and diffusion in the ZIKAV research network; (iv) Brazil was the single LAC country filing patents, mostly represented by independent inventors and low-tech patents. The paper advocates the need for a continued interdisciplinary approach to improve LAC countries ability to prevent, prepare for and control future outbreaks.
Assuntos
Pesquisa Biomédica/tendências , Epidemias/estatística & dados numéricos , Infecção por Zika virus/epidemiologia , Zika virus , Brasil , Região do Caribe/epidemiologia , Surtos de Doenças , Saúde Global , Humanos , América Latina/epidemiologia , Saúde Pública/tendências , Fatores Socioeconômicos , Infecção por Zika virus/prevenção & controleRESUMO
BACKGROUND: Cryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance. OBJECTIVES: The goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field. METHODS: We identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence. FINDINGS: Patenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts. CONCLUSION: The low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.
Assuntos
Antifúngicos , Criptococose/tratamento farmacológico , Desenvolvimento de Medicamentos , Patentes como Assunto/estatística & dados numéricos , Humanos , Patentes como Assunto/legislação & jurisprudênciaRESUMO
BACKGROUND Cryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance. OBJECTIVES The goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field. METHODS We identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence. FINDINGS Patenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts. CONCLUSION The low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.
Assuntos
Humanos , Meningite Criptocócica/terapia , Criptococose , Cryptococcus , /organização & administraçãoRESUMO
INTRODUCTION: Cryptococcosis is one of the most devastating human fungal infections. Despite its impact, none of the standard antifungals were developed after 1990. New, improved, less toxic, affordable and widely available treatment is, therefore, imperative. AREAS COVERED: This review offers an insight into technological developments for cryptococcosis disclosed in patent literature. From a broad search of patent documents claiming cryptococcosis treatment and having earliest priority between 1995 and 2015, we selected and summarized compounds/molecules (i) revealed in documents disclosing in vivo activity against Cryptococcus spp. or (ii) found in the pipeline of companies that appeared as assignees in our patent search. This information was complemented with data on compounds under development for this indication from the database Integrity (Clarivate Analytics). EXPERT OPINION: This review demonstrates that drug development against cryptococcosis is discrete. However, it also shows that the existing development is not focused on a single class of molecules, but on different types of molecules with distinct fungal targets, reflecting the complexity of generating novel anti-cryptococcal tools. Given the intrinsic difficulties and high costs of drug development and the evident market failure in this field, we consider drug repurposing the most promising avenue for cryptococcosis treatment.
Assuntos
Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Desenho de Fármacos , Animais , Antifúngicos/toxicidade , Criptococose/microbiologia , Cryptococcus/efeitos dos fármacos , Reposicionamento de Medicamentos , Humanos , Patentes como AssuntoRESUMO
INTRODUCTION: Angiotensin-(1-7) is a key component of the Renin-Angiotensin System, which can counter-regulate several deleterious effects caused by angiotensin II. Due to the potential for therapeutic use, several of its actions are specifically described in patents. AREAS COVERED: In this review, the authors describe a plethora of therapeutic uses for Angiotensin-(1-7), claimed and supported by experimental evidence in patent documents and applications. EXPERT OPINION: The clinical potential of Angiotensin-(1-7) as a therapeutic agent to treat several pathologies is evidenced by the variety of patents and clinical trials involving this peptide. Cancer treatment is one of the most advanced therapeutic areas, but clinical studies are also available in several other areas, such as cardiovascular, hematological, transplantation, surgical and medical procedures.
Assuntos
Angiotensina I/uso terapêutico , Ensaios Clínicos como Assunto , Fragmentos de Peptídeos/uso terapêutico , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Desenho de Fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Patentes como Assunto , Fragmentos de Peptídeos/metabolismoRESUMO
Trypanosoma cruzi, the causative agent of Chagas disease, is an obligatory intracellular parasite with a digenetic life cycle. Due to the variety of host environments, it faces several sources of oxidative stress. In addition to reactive oxygen species (ROS) produced by its own metabolism, T. cruzi must deal with high ROS levels generated as part of the host's immune responses. Hence, the conclusion that T. cruzi has limited ability to deal with ROS (based on the lack of a few enzymes involved with oxidative stress responses) seems somewhat paradoxical. Actually, to withstand such variable sources of oxidative stress, T. cruzi has developed complex defence mechanisms. This includes ROS detoxification pathways that are distinct from the ones in the mammalian host, DNA repair pathways and specialized polymerases, which not only protect its genome from the resulting oxidative damage but also contribute to the generation of genetic diversity within the parasite population. Recent studies on T. cruzi's DNA repair pathways as mismatch repair (MMR) and GO system suggested that, besides a role associated with DNA repair, some proteins of these pathways may also be involved in signalling oxidative damage. Recent data also suggested that an oxidative environment might be beneficial for parasite survival within the host cell as it contributes to iron mobilization from the host's intracellular storages. Besides contributing to the understanding of basic aspects of T. cruzi biology, these studies are highly relevant since oxidative stress pathways are part of the poorly understood mechanisms behind the mode of action of drugs currently used against this parasite. By unveiling new peculiar aspects of T. cruzi biology, emerging data on DNA repair pathways and other antioxidant defences from this parasite have revealed potential new targets for a much needed boost in drug development efforts towards a better treatment for Chagas disease.
Assuntos
Antioxidantes/metabolismo , Dano ao DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/metabolismo , Doença de Chagas/parasitologia , Doença de Chagas/terapia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Oxirredução , Trypanosoma cruzi/genética , Trypanosoma cruzi/imunologiaRESUMO
We have previously shown that various species of Leishmania produce a lytic activity, which, in Leishmania amazonensis, is mediated by a pore-forming cytolysin, called leishporin. It is toxic for macrophages in vitro and optimally active at pH 5.0 to 5.5 and at 37 °C, suggesting that it might be active inside phagolysosomes. Leishporin from both L. amazonensis (a-leishporin) and Leishmania guyanensis (g-leishporin) can be activated by proteases, suggesting either a limited proteolysis of an inactive precursor or a proteolytic degradation of a non-covalently linked inhibitor. Here, we show that both a- and g-leishporin are also activated in dissociating conditions, indicating the second hypothesis as the correct one. In fact, we further demonstrated that inactive leishporin is non-covalently associated with an inhibitor, possibly more than one oligopeptide that, when removed, renders leishporin hemolytically active. This activation was shown to be the result of both the improvement of leishporin's ability to bind to phospholipids and the emergence of its pore-forming ability. In vitro results demonstrate that leishporin can be released by the parasites, as they evolve in axenic cultures, in an inactive form that can be activated. These results are compatible with our hypothesis that leishporin can be activated in the protease-rich, low pH, and dissociating environment of parasitophorous vacuoles, leading to disruption of both vacuoles and plasma membranes with the release of amastigotes.
Assuntos
Eritrócitos/parasitologia , Leishmania/metabolismo , Leishmaniose/parasitologia , Lipídeos de Membrana/metabolismo , Proteínas de Protozoários/metabolismo , Animais , Membrana Celular/metabolismo , Citotoxinas/metabolismo , Ativação Enzimática , Eritrócitos/fisiologia , Hemólise , Humanos , Concentração de Íons de Hidrogênio , Peptídeo Hidrolases/metabolismo , Ligação Proteica , TemperaturaRESUMO
Components of the DNA mismatch repair (MMR) pathway are major players in processes known to generate genetic diversity, such as mutagenesis and DNA recombination. Trypanosoma cruzi, the protozoan parasite that causes Chagas disease has a highly heterogeneous population, composed of a pool of strains with distinct characteristics. Studies with a number of molecular markers identified up to six groups in the T. cruzi population, which showed distinct levels of genetic variability. To investigate the molecular basis for such differences, we analyzed the T. cruzi MSH2 gene, which encodes a key component of MMR, and showed the existence of distinct isoforms of this protein. Here we compared cell survival rates after exposure to genotoxic agents and levels of oxidative stress-induced DNA in different parasite strains. Analyses of msh2 mutants in both T. cruzi and T. brucei were also used to investigate the role of Tcmsh2 in the response to various DNA damaging agents. The results suggest that the distinct MSH2 isoforms have differences in their activity. More importantly, they also indicate that, in addition to its role in MMR, TcMSH2 acts in the parasite response to oxidative stress through a novel mitochondrial function that may be conserved in T. brucei.
Assuntos
Proteína 2 Homóloga a MutS/metabolismo , Estresse Oxidativo , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/genética , Adenosina Trifosfatases/metabolismo , Cisplatino/farmacologia , Reagentes de Ligações Cruzadas/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA , DNA Mitocondrial/genética , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Peróxido de Hidrogênio/farmacologia , Dados de Sequência Molecular , Proteína 2 Homóloga a MutS/genética , Mutação , Oxidantes/farmacologia , Proteínas de Protozoários/genética , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/genética , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Trypanosomes are unicellular eukaryotes that cause disease in humans and other mammals. Trypanosoma cruzi and Trypanosoma brucei are the causative agents, respectively, of Chagas disease in the Americas and sleeping sickness in sub-Saharan Africa. To better comprehend the interaction of these parasites with their hosts, understanding the mechanisms involved in the generation of genetic variability is critical. One such mechanism is mismatch repair (MMR), which has a crucial, evolutionarily conserved role in maintaining the fidelity of DNA replication, as well as acting in other cellular processes, such as DNA recombination. Here we have attempted to complement T. brucei MMR through the expression of MSH2 from T. cruzi. Our results show that T. brucei MSH2-null mutants are more sensitive to hydrogen peroxide (H2O2) than wild type cells, suggesting the involvement of MSH2 in the response to oxidative stress in this parasite. This phenotype is reverted by the expression of either the T. cruzi or the T. brucei MSH2 protein in the MSH2-null mutants. In contrast, MMR complementation, as assessed by resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and microsatellite instability, was not achieved by the heterologous expression of T. cruzi MSH2. This finding, associated to the demonstration that mutation of MLH1, another component of the MMR system, did not affect sensitivity of T. brucei cells to H2O2, suggests an additional role of MSH2 in dealing with oxidative damage in these parasites, which may occur independently of MMR.
Assuntos
Reparo de Erro de Pareamento de DNA , Proteína 2 Homóloga a MutS/genética , Estresse Oxidativo , Proteínas de Protozoários/genética , Trypanosoma brucei brucei/genética , Trypanosoma cruzi/genética , Animais , Dano ao DNA , Genes de Protozoários , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Instabilidade de Microssatélites , Mutação , Recombinação GenéticaRESUMO
The bacteria Escherichia coli has been widely employed in studies of eukaryotic DNA repair genes. Several eukaryotic genes have been cloned by functional complementation of mutant lineages of E. coli. We examined the similarities and differences among bacterial and eukaryotic DNA repair systems. Based on these data, we examined tools used for gene cloning and functional studies of DNA repair in eukaryotes, using this bacterial system as a model.