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A Targeted and Protease-Activated Genetically Encoded Melittin-Containing Particle for the Treatment of Cutaneous and
Madiha Habib1, Jiale Zheng1, Chin-Fung Chan2
1School of Life Sciences and Center of Novel Biomaterials, The Chinese University of Hong Kong, Shatin, Hong Kong SAR 999077, China.
Abstract:
Intracellular infections are difficult to treat, as pathogens can take advantage of intracellular hiding, evade the immune system, and persist and multiply in host cells. One such intracellular parasite, Leishmania, is the causative agent of leishmaniasis, a neglected tropical disease (NTD), which disproportionately affects the world's most economically disadvantaged. Existing treatments have relied mostly on chemotherapeutic compounds that are becoming increasingly ineffective due to drug resistance, while the development of new therapeutics has been challenging due to the variety of clinical manifestations caused by different Leishmania species. The antimicrobial peptide melittin has been shown to be effective in vitro against a broad spectrum of Leishmania, including species that cause the most common form, cutaneous leishmaniasis, and the most deadly, visceral leishmaniasis. However, melittin's high hemolytic and cytotoxic activity toward host cells has limited its potential for clinical translation. Herein, we report a design strategy for producing a melittin-containing antileishmanial agent that not only enhances melittin's leishmanicidal potency but also abrogates its hemolytic and cytotoxic activity. This therapeutic construct can be directly produced in bacteria, significantly reducing its production cost critical for a NTD therapeutic. The designed melittin-containing fusion crystal incorporates a bioresponsive cathepsin linker that enables it to specifically release melittin in the phagolysosome of infected macrophages. Significantly, this targeted approach has been demonstrated to be efficacious in treating macrophages infected with L. amazonensis and L. donovani in cell-based models and in the corresponding cutaneous and visceral mouse models.
Insights
A novel melittin-based fusion crystal effectively targets intracellular Leishmania parasites, enhancing potency while reducing host cell toxicity. This cost-effective therapeutic shows promise for treating leishmaniasis, a neglected tropical disease.
Area of Science:
- Biochemistry
- Parasitology
- Drug Development
Background:
- Intracellular pathogens like Leishmania cause neglected tropical diseases (NTDs), with treatments facing drug resistance and limited efficacy.
- Melittin, an antimicrobial peptide, shows in vitro activity against Leishmania but has high host cell toxicity, hindering clinical use.
- Developing new Leishmania therapeutics is challenging due to diverse clinical presentations and drug resistance.
Purpose of the Study:
- To design a novel melittin-containing agent with enhanced leishmanicidal activity and reduced host cell toxicity.
- To develop a cost-effective production method for a new antileishmanial therapeutic suitable for NTDs.
- To create a targeted delivery system for melittin release specifically within infected host cells.
Main Methods:
- Engineered a melittin-containing fusion crystal with a bioresponsive cathepsin linker for targeted release.
- Produced the therapeutic construct directly in bacteria to reduce production costs.
- Evaluated the agent's efficacy in cell-based models and cutaneous and visceral mouse models of leishmaniasis.
Main Results:
- The designed agent demonstrated enhanced melittin potency against Leishmania parasites.
- Hemolytic and cytotoxic activity of melittin towards host cells was significantly abrogated.
- The fusion crystal effectively treated Leishmania-infected macrophages and demonstrated efficacy in mouse models for both cutaneous and visceral leishmaniasis.
Conclusions:
- A novel, bacteria-produced melittin-based fusion crystal offers a promising strategy for treating leishmaniasis.
- Targeted delivery via a cathepsin linker enhances therapeutic efficacy while minimizing host toxicity.
- This approach presents a cost-effective and potentially transformative treatment for neglected tropical diseases like leishmaniasis.
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