RESUMO
The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a joint global effort to develop vaccines and other treatments that could mitigate the negative effects and the rapid spread of the virus. Single-domain antibodies derived from various sources, including cartilaginous fish, camelids, and humans, have gained attention as promising therapeutic tools against coronavirus disease 2019. Shark-derived variable new antigen receptors (VNARs) have emerged as the smallest naturally occurring antigen-binding molecules. Here, we compile and review recent published studies on VNARs with the capacity to recognize and/or neutralize SARS-CoV-2. We found a close balance between the use of natural immune libraries and synthetic VNAR libraries for the screening against SARS-CoV-2, with phage display being the preferred display technology for the selection of VNARs against this virus. In addition, we discuss potential modifications and engineering strategies employed to improve the neutralization potential of VNARs, such as exploring fusion with the Fc domain of human Immunoglobulin G (IgG) to increase avidity and therapeutic potential. This research highlights the potential of VNARs as powerful molecular tools in the fight against infectious diseases.
Assuntos
COVID-19 , Tubarões , Animais , Humanos , SARS-CoV-2 , Técnicas de Visualização da Superfície Celular , Receptores de AntígenosRESUMO
Research into various proteins capable of blocking metabolic pathways has improved the detection and treatment of multiple pathologies associated with the malfunction and overexpression of different metabolites. However, antigen-binding proteins have limitations. To overcome the disadvantages of the available antigen-binding proteins, the present investigation aims to provide chimeric antigen-binding peptides by binding a complementarity-determining region 3 (CDR3) of variable domains of new antigen receptors (VNARs) with a conotoxin. Six non-natural antibodies (NoNaBodies) were obtained from the complexes of conotoxin cal14.1a with six CDR3s from the VNARs of Heterodontus francisci and two NoNaBodies from the VNARs of other shark species. The peptides cal_P98Y vs. vascular endothelial growth factor 165 (VEGF165), cal_T10 vs. transforming growth factor beta (TGF-ß), and cal_CV043 vs. carcinoembryonic antigen (CEA) showed in-silico and in vitro recognition capacity. Likewise, cal_P98Y and cal_CV043 demonstrated the capacity to neutralize the antigens for which they were designed.
Assuntos
Conotoxinas , Gastrópodes , Tubarões , Animais , Fator A de Crescimento do Endotélio Vascular , Anticorpos , Antígenos , Peptídeos , Proteínas de TransporteRESUMO
Sea snails of the genus Conus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since Conus toxins were discovered in the 1960s, their biological activity has been thought to have high pharmaceutical potential that could be explored beyond the limits of academic laboratories. We reviewed 224 patent documents related to conotoxins and conopeptides globally to determine the course that innovation and development has taken over the years, their primary applications, the technological trends over the last six years, and the leaders in the field, since the only previous patent review was performed in 2015 and focused in USA valid patents. In addition, we explored which countries/territories protect their inventions and patents and the most relevant collaborations among assignees. We also evaluated whether academia or pharmaceutical companies are the future of conotoxin research. We concluded that the 224 conotoxin patents reviewed in this study have more academic value than industrial value, which was noted by the number of active patents that have not yet been licensed and the contributions to medical research, especially as tools to study neuropathic pain, inflammation, immunology, drug design, receptor binding sites, cancer, neurotransmission, epilepsy, peptide biosynthesis, and depression. The aim of this review is to provide an overview of the current state of conotoxin patents, their main applications, and success based on the number of licensing and products in the market.
Assuntos
Conotoxinas , Caramujo Conus , Animais , Humanos , Indústrias , Preparações FarmacêuticasRESUMO
The FDA's approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the CaV1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic ß-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas's capability to produce insulin is still effective.