BR-102024017848-A2 - Use of Annexin A1 mimetic peptide and topical pharmaceutical formulation for the treatment of cutaneous leishmaniasis.

Abstract

The present technology relates to the use of an Annexin A1 mimetic peptide called Ac-2-26 in the production of drugs for the treatment of cutaneous leishmaniasis and a topical pharmaceutical formulation based on the peptide.

Inventors

• ANA PAULA SALLES MOURA FERNANDES
• LIRLÂNDIA PIRES DE SOUSA
• TIAGO QUEIROGA NERY RICOTTA
• LILIANE MARTINS DOS SANTOS
• MÍRIAM CONCEIÇÃO DE SOUZA TESTASICCA
• LEANDRO GONZAGA DE OLIVEIRA
• JULIANA PRISCILA VAGO DA SILVA
• GISELE ASSIS CASTRO GOULART

Assignees

• UNIVERSIDADE FEDERAL DE MINAS GERAIS

Dates

Publication Date

20260310

Application Date

20240829

Claims (2)

1. 1. USE OF ANNEXIN A1 MIMETIC PEPTIDE defined by SEQ ID No. 1, characterized by its use in the production of medicines for the treatment of cutaneous leishmaniasis.
2. 2. TOPICAL PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF CUTANEOUS LEISHMANIASIS, using the peptide defined in claim 1, characterized by comprising: a. Polyethylene glycol 400 (PEG 400) from 16% to 24% v/v; b. Propylene glycol at 32% to 48% v/v; c. Diethylene glycol monoethyl ether (DEGEE) 16% to 24% v/v; d. MilliQ water at 16% to 24% v/v; e. Xanthan gum at 2.4% to 3.6% w/v; f. Synthetic peptide defined by SEQ ID No. 1 at 320 to 480 μg/ml.

Description

[01] The present technology relates to the use of an Annexin A1 mimetic peptide called Ac-2-26 in the production of medicines for the treatment of cutaneous leishmaniasis and a topical pharmaceutical formulation based on the peptide. [02] Leishmaniasis is the clinical term that encompasses a set of diseases caused by protozoa of the genus Leishmania. Currently, more than twenty species of this parasite are known to infect humans, in addition to species that infect other mice and non-pathogenic species. Being a zoonotic disease, the transmission of the parasite to humans and other mammalian hosts occurs through the bite of female sandflies belonging to the genera Lutzomyia (Old World) and Phlebotomus. [03] Leishmaniasis occurs on all continents except Antarctica, with endemic areas inhabited by more than one billion people, who are at risk of infection. Estimates updated annually show more than one million new cases of Cutaneous Leishmaniasis (CL) and 30,000 new cases of Visceral Leishmaniasis (VL) spread throughout the world. [04] The risk of infection is increased when there is poor basic sanitation conditions, lack of investment in population health and lack of planning for land use, which occur mainly in areas where Leishmania is endemic, thus demonstrating a strong correlation between the prevalence of the disease and the socioeconomic conditions of the affected areas. [05] Treatment of Cutaneous Leishmaniasis (CL) can be done with various drugs, each with its own properties and limitations. First-line medications include pentavalent antimony (Sb5+), one of the first drugs used and the basis of anti-Leishmania chemotherapy. Second-line drugs, such as pentamidine and amphotericin, are also used to treat this infection. Miltefosine, an anticancer agent, has been registered for the treatment of VL and CL. Oral efficacy and short treatment period were the main advantages of this drug. However, the treatment has its limitations. Sb5+ salts have had their use limited due to cardiac and renal toxicity in several patients with Leishmaniasis. Sb5+ is rapidly absorbed by the body and almost 90% of it is excreted in the first 48 hours by the kidneys. Consequently, there is a need to administer higher doses of the drug containing this ion, in a continuous regimen, in order to guarantee a higher level of antimony in the tissues and thus obtain the effectiveness of the treatment. [06] Amphotericin B deoxycholate (AmB-D) in clinical treatment has been limited due to chronic and acute adverse effects such as fever, chills, nephrotoxicity, hypokalemia, myocarditis, and even death. Furthermore, inappropriate use of medication has led to drug resistance. Finally, among the therapeutic options, the choice of medication depends on several factors, including the clinical form of the disease, concomitant pathologies, parasite species, geographic location, and safety for the patient's clinical profile, always with the aim of curing the skin lesion and preventing late mucosal damage. [07] As treatment for LT presents numerous limitations, including difficulty of adherence, adverse effects and toxicity of the drugs used, the present invention aims at the development of a safe, effective and easy-to-apply topical treatment. The present technology deals with the use of an Annexin A1 mimetic peptide called Ac-2-26 in the production of drugs for the treatment of cutaneous leishmaniasis and a topical pharmaceutical formulation based on the peptide and presents as advantages over the state of the art a safe treatment, with low toxicity and the topical formulation is easy to apply to treat cutaneous leishmaniasis. [08] Annexin A1 is a protein involved in the regulation of several cellular processes including apoptosis, cell differentiation and modulation of the inflammatory response. The protein has also been described as being involved in cancer progression through interactions with immune cells. [09] Pharmacological analyses identified the first 24 amino acids in the amino-terminal portion of annexin A1 as the most important region. The peptide containing this sequence was named Ac-2-26. It has been demonstrated that the Ac-2-26 peptide retains the anti-inflammatory and protective activity of complete annexin A1, blocking cell migration and the production of pro-inflammatory cytokines in a murine model of peritonitis, acute skin inflammation, and ischemia-reperfusion injury (Perretti M, et al., Lipocortin-1 fragments inhibit neutrophil accumulation and neutrophil-dependent edema in the mouse. A qualitative comparison with an anti-CD11b monoclonal antibody. J Immunol. 1993 Oct 15;151(8):4306-14. Lim LH et al. Promoting detachment of neutrophils adherent to murine postcapillary venules to control inflammation: effect of lipocortin 1. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24): 14535-9. [10] Annexin A1 has been described for different uses. Patent document WO2022038258, entitled “Annexin A1-derived polypeptide analogues”, with a prior