BR-102024018193-A2 - Bio-inspired peptide from social wasp venom associated with nanotechnology and its use as an antiepileptic and neuroprotective agent.

Abstract

The present invention relates to a pharmaceutical composition encompassing the fields of neuropharmacology and nanotechnology. Venom-derived peptides have been excellent candidates for the development of new, safer drugs with fewer side effects, mainly due to some intrinsic characteristics and chemical and biological diversity, including: high potency, excellent selectivity, low chemical toxicity, and immunogenicity. The present technology proposes an antiepileptic and neuroprotective peptide, designed from a described peptide from the venom of social wasps of the genus Polybia, which was synthesized and incorporated into nanotechnology. To this end, the nanotechnology containing the peptide was evaluated in mice subjected to the chronic model of Status Epilepticus (SE) induced by pilocarpine. Treatment with the nanotechnological innovation proved effective in reducing epileptic seizures and maintained its stability throughout the study.

Inventors

• MARCIA RENATA MORTARI
• JOÃO DAIVISON SILVA RAMALHO
• Graziella Anselmo Joanitti
• ALICIA SIMALIE OMBREDANE
• ADOLFO CARLOS BARROS DE SOUZA
• FRANCISCA VALÉRIA BEZERRA SAMPAIO MARQUES
• SAMUEL SILVA MORAES
• VICTORIA MONGE-FUENTES
• LILIAN DOS ANJOS CARNEIRO
• GABRIEL AVOHAY ALVES CAMPOS

Assignees

• FUNDAÇÃO UNIVERSIDADE DE BRASILIA
• BIOINTECH BIOTECNOLOGIA LTDA

Dates

Publication Date

20260317

Application Date

20240904

Claims (5)

1. 1. PHARMACEUTICAL COMPOSITION characterized by encapsulation of the Neurovespina peptide (SEQID N1) in a lipid nanoemulsion.
2. 2. PROCESS FOR PRODUCING NEUROVESPINA LIPID NANOEMULSION, according to claim 1, characterized by comprising the following steps: A) Dissolving 12 mg of Neurovespina (SEQID N1) in 10 mL of absolute ethanol, followed by ultrasonic homogenization in a bath for 10 minutes; B) Adding Neurovespina (SEQID N1) in absolute ethanol to 388.8 mg of lecithin dissolved in 194.4 mg of olive oil; C) Drying the solution in a rotary evaporator at temperatures between 60°C and 70°C and a pressure of 50 mBar, forming a film; D) Resuspending the film in a solution containing saline solution with phosphate buffer and 25.2 mg of chitosan in an ice bath.
3. 3. USE OF THE PHARMACEUTICAL COMPOSITION, according to claims 1 and 2, characterized by producing a neuroprotective effect.
4. 4. USE OF THE PHARMACEUTICAL COMPOSITION, according to claims 1 and 2, characterized by being used in the production of a medicament for the treatment of neurological diseases, such as Temporal Lobe Epilepsy (Refractory Epilepsy).
5. 5. USE OF THE PHARMACEUTICAL COMPOSITION, according to claims 1 and 2, characterized by being used in the production of a medicament for the treatment of neurological diseases associated with neurodegeneration.

Description

FIELD OF THE INVENTION [001] The present invention is situated in the field of neuropharmacology and nanotechnology and relates to the use of peptides for the treatment of epilepsy. This technology proposes the incorporation of an antiepileptic and neuroprotective peptide, called neurovespin, into lipid nanoparticles. STATE OF THE ART [002] The phylum Arthropoda is the largest in the animal kingdom, containing a wide variety of life forms. The class Insecta, by itself, has described more than one million species, exhibiting a remarkable variety in terms of morphology, behavior, and habits. Within the insect group, wasps, bees, and ants belong to the order Hymenoptera, which, combined, represent a set of more than 200,000 species (BRANSTETTER, M.G., et al. Current opinion in insect science, v. 25, p. 65-75, 2018). [003] Among social wasps, Polybia occidentalis stands out for its aggressiveness and its exclusive occurrence in neotropical regions. Similar to most social wasps, this species uses its venom both for defense and for the protection of the nest. Its main food sources consist of insects, including hemipterans, diptera, hymenoptera and lepidopterans, in their larval stages. When captured, prey is transported to the nest, where it is used to feed the young, or stored for later use (MORTARI, M.R., et al. Basic & clinical pharmacology & toxicology, v. 97(5), p. 289-295, 2005). [004] In order to explore the biochemical and pharmacological relevance of wasp venom, especially that of the species Polybia occidentalis, studies have shown that, after denaturation, venom administered intracerebroventricularly (i.c.v.) in rats had the ability to protect the animals against epileptic seizures induced by bicuculline, picrotoxin and kainic acid (MORTARI, M.R., et al. Basic & clinical pharmacology & toxicology, v. 97(5), p. 289-295, 2005). [005] After fractionation and structural characterization of the venom components, a new antiepileptic peptide was obtained, named Occidentalina-1202 (OcTx-1202), consisting of nine amino acid residues (Glu-Gln-Tyr-Met-Val-Ala-Phe-Trp-Met-NH2). The OcTx-1202 peptide showed a potent anticonvulsant and neuroprotective effect in an acute seizure induction model with kainic acid in rats and a chronic pilocarpine-induced model in mice that mimics a refractory epilepsy model (MORTARI, M.R., et al. Brain Communications, v. 5(1), fcad016, 2023). [006] Patent BR102014004728A2 describes a development in research with OcTx-1202 where a synthetic analogue, the Neurovespina peptide, was created with the sequence PyrGlu-Gln-Met-Trp-Ala-Val-Phe-Trp-Met-NH2, but without the effects of the present technology, or the application of nanotechnology and the new uses claimed herein. Its sequence was made by replacing glutamic acid with pyroglutamic acid, in order to increase its affinity with membrane receptors of the Cerebral Nervous System (CNS), and tyrosine was removed from the third position and tryptophan was added to the fourth position, to facilitate the passage of the peptide through the BBB by amplifying its nonpolar characteristic. [007] Based on alterations in the sequence and obtaining the Neurovespina peptide, it was shown that the antiepileptic activity is approximately six times more potent than that of OcTx-1202 in a model of acute seizure induction by kainic acid (DOS ANJOS, L.C. University of Brasília, Dissertation (Master's in Animal Biology), 2013). Similar data were obtained in a chronic model of pilocarpine-induced temporal lobe epilepsy (refractory epilepsy), with the Neurovespina peptide demonstrating a potent antiepileptic effect (DOS ANJOS, L.C. University of Brasília, Thesis (Doctorate in Health Sciences), 2017). However, in both cases, the peptide was administered by parenteral injection, a route that typically causes discomfort and requires great care against infections, while the present technology allows for intranasal administration. [008] One strategy to improve drug delivery to the site of action via other routes of administration involves the use of nanotechnology-based delivery systems. Nanotechnology encompasses a wide range of applications, from adapting routes of administration to optimizing their efficiency, protecting against degradation, increasing solubility, creating innovative formulations, among many other possibilities, and is considered a promising alternative, mainly due to the ability of the nanoscale to increase drug bioavailability (SAEEDI, M., et al. Biomedicine & pharmacotherapy, v. 111, p. 666-675, 2019). [009] Several varieties of nanocarriers demonstrate the ability to improve the release profile of a drug, allowing its transport to the specific site in order to guarantee its therapeutic activity with maximum safety. Among these nanocarriers are micelles, liposomes, polymeric nanoparticles and lipid nanoparticles (ALOTAIBI, B. S., et al. International Journal of Nanomedicine, v. 16, p. 7517-753, 2021). [010] Patent application CN103665099A entit