Figure - available from: Frontiers in Microbiology
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Potential of Synthetic biology tools as therapeutics in leishmaniasis. (A) CRISPR/Cas9 mechanism to mutate parasite. (B) Engineering synthekines to regulate host immune response to eliminate parasite. (C) Modulation of parasite through pLEXSY system (D) Bi-stable toggle switch as multi-therapeutic approach to combat resistance in parasite (E) Cocktail of parasite antigens can be cloned to modulate host macrophage response. (F) Histones of parasite can be engineered in synthetic circuit to develop stronger immune response. (G) Operon may be modulated to express at spatio-temporal level to express therapeutic.
Source publication
Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the Leishmania genus. Despite the efforts to control and treat the disease, it still remains a major public health problem in many countries. Synthetic biology is a rapidly evolving interdisciplinary field that combines biology, engineering, and computer science to desig...
Citations
... Although SBDD studies supplement high-throughput screening and pharmacokinetic optimization, owing to the prevailing view of limited validated targets, certain SBDD strategies have notably contributed to emerging drug candidates with substantial future potential [103]. Synthetic biology involves an interdisciplinary field merging biology, engineering, and computer science, which recently showed potential in developing innovative methods to tackle leishmaniasis [104]. Finally, according to Griensven et al. [102], it is important to emphasize that optimizing the efficacy and extending the lifespan of new treatments necessitates the inclusion of pharmacological substudies for proper dosing and the establishment of systems for the early detection of drug resistance in future research. ...
In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m2) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day “wash-out” period; Study B: nine dogs received three IV doses of 150 mg/m2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes–alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)–and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m2. After single doses of 17-AAG (50–250 mg/m2), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0–8 h μg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m2. Increased levels of liver enzymes–ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)–and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0–48 h were 5254 ± 2784 μg/mL and 6850 ± 469 μg/mL × h in plasma and 736 ± 294 μg/mL and 7382 ± 1357 μg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m2, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.
