Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a disease that is characterized by a spectrum of clinical manifestations ranging from ulcerative skin lesions to fatal visceral infections. Leishmaniasis is a poverty-related disease and is associated with malnutrition, displacement, poor housing, illiteracy, gender discrimination, weakness of the immune system and lack of resources. Leishmaniasis is further compromised by the emergence of co-infection with human immunodeficiency virus (HIV) in endemic areas. Globally, there are an estimated 1.52 million new cases of leishmaniasis and 80,000 deaths each year, and 350 million people are at risk of infection and disease. In the absence of vaccination, chemotherapy, together with vector control, remains one of the most important elements in the control of leishmaniasis. However, this strategy is seriously threatened by the high toxicity of clinical drugs and the rampant increase of resistance in the field. As leishmaniasis is a disease of poverty, pharmaceutical companies have had limited incentive for the search of novel anti-leishmanial drugs because there would be low economic return on their investment. The goal of this SBIR application is to develop an affordable and effective antileishmanial ointment for treating cutaneous leishmaniasis (CL) in both developed and developing areas of the world. Our team recently discovered that zinc(II)-dipicolylamine (ZnDPA) complexes have strong antileishmanial activity against Leishmania major one of the causative agents of CL. Molecular Targeting Technologies Inc. will develop ointment formulations of ZnDPA and the team at the University of Notre Dame will test these ointments in an in vivo model of CL that takes advantage of a genetically modified L. major strain which stably express a red fluorescent mCherry protein. Furthermore, the proposed studies on skin toxicity and biodistribution of ZnDPA will be significant for a successful clinical translation.
Public Health Relevance Statement: Leishmania spp. are parasitic protozoa responsible for a spectrum of diseases known as leishmaniasis. Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization (WHO). There are few drugs available for the treatment of these diseases, and most are expensive and highly toxic. This project will apply new technology to test new compounds that can be developed into real solutions for the control of leishmaniasis.
Project Terms: Acetates; Address; Adverse effects; Aftercare; Animal Model; Anions; Area; Biodistribution; Biological Assay; Blood Circulation; Cessation of life; Chemicals; chemotherapy; Clinical; clinical translation; clinically relevant; co-infection; cohort; Complex; Cutaneous; Cutaneous Leishmaniasis; Data; Dermal; Development; Disease; drug development; drug discovery; Drug Industry; Economics; Elements; Ethanol; Excipients; Exhibits; expectation; experimental study; FDA approved; Female; Fluorescence; Formulation; Gel; Goals; Harvest; histological stains; HIV; Housing; Human; illiteracy; Image; Immune system; In Vitro; in vivo Model; Inbred BALB C Mice; Incentives; Infection; International Health Problems; Investments; Irritants; Leishmania; Leishmania major; Leishmaniasis; Lesion; Malnutrition; Measures; Methods; Molecular Target; Monitor; Morbidity - disease rate; mortality; mouse model; Mus; Necrosis; new technology; Nitrates; novel; Octanols; Ointments; Organ; Parasites; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Polyethylene Glycols; Poverty; Property; Propylene Glycols; Proteins; Protozoa; Reporting; Resistance; Resources; Risk; Sampling; Sex Discrimination; Skin; skin irritation; skin lesion; Skin Ulcer; Slice; Small Business Innovation Research Grant; Stains; standard measure; standard of care; Structure; Technology; Testing; Tissue Viability; Tissues; Topical application; Toxic effect; Toxicology; Universities; Vaccination; vector control; Visceral; World Health Organization; Zinc
