Mitochondrial disorders have heterogeneity and may manifest at any age. The challenges in therapy are compounded by the multi-organ involvement observed in many mitochondrial diseases. Small molecules drug discovery platform, which in drug discovery for mitochondrial disorders are an essential drug development tool, and Protheragen provides small molecule drug discovery and development services to accelerate the research process for clients.
Small Molecule Drugs for Mitochondrial Diseases
The therapeutic of mitochondrial diseases comprises the use of numerous small molecule drugs, each of which has a specific role in the mitochondrial functional and cellular metabolism.
- Molecules Bypassing Mitochondrial Complex I Deficiency
Idebenone has been studied in other diseases for its effects as an electron carrier and antioxidant, more so in individuals with mitochondrial and some neurodegenerative diseases.
- Agents Enhancing Electron Transfer Chain Function
Some individuals suffering from specific types of mitochondrial diseases have shown positive responses to therapy with riboflavin and coenzyme Q10 (CoQ10). Dichloroacetate (DCA) and thiamine increase the activity of pyruvate dehydrogenase, thus facilitating entry into the citric acid cycle. Sonlicromanol, lipoic acid, and glutathione strengthen mitochondrial function and antioxidant defenses.
- Agents Regulating NADH/NAD+ Rati
Using regulatory compounds such as pyruvate, AICAR, nicotinamide riboside, and acipimox to correct the disturbed NADH/NAD+ balance while potentially improving glycolysis and mitochondrial function.
Fig.1 NAD+-Mediated Rescue of Mitochondrial Function. (Russell, O. M., et al., 2020)
- Agents Restoring Nitric Oxide Production
Arginine and citrulline act as NO precursors, potentially benefiting conditions like stroke-like episodes in MELAS syndrome.
- Agents Regulating Autophagy
Rapamycin and urolithin A stimulate mitophagy, offering potential therapeutic benefits in mitochondrial disorders.
- Agents as Cardiolipin Protectors
Elamipretide binds to cardiolipin, preserving its function and improving cardiac mitochondrial function.
- Agents as Energy Buffer
Creatine and taurine stabilize cellular bioenergetics and show neuroprotective effects in various conditions.
Fig.2 Small molecules for mitochondrial disorders. (Meng, L., et al., 2023)
Our Services
The development of small molecule drugs is an accomplished procedure highly reliant on the integration of diverse fields such as chemistry, biology, and pharmacology. Protheragen's staff has the experience and requisite resources that allow the customer to produce accurate results in the development of small molecule drugs that target various mitochondrial diseases.
Discovery and Screening
- Through virtual and high-throughput procedures and rational drug design, attempt to identify small molecule compounds that show promise.
- After identifying promising compounds, perform preliminary screening tests to measure their efficacy, selectivity, and safety considerations.
- Focus on lead compounds that are more active against relevant molecular targets or pathways associated with mitochondrial diseases.
Lead Optimization
- Conduct medicinal chemistry experiments with lead compounds to optimize chemical structures to increase potency, selectivity, and optimal pharmacokinetics.
- Test the lead compounds in vitro and in vivo for efficacy, toxicity, and metabolic stability.
- Repetitively refine the chemical structure through structure-activity relationship (SAR) studies to enhance drug-like properties and minimize adverse effects.
Preclinical Development
- Conduct extensive preclinical studies to determine the safety and effectiveness of the lead compounds in relevant disease models: mitochondrial disease cell lines and animal models.
- Assess the pharmacokinetics (PK), pharmacodynamics (PD), and toxicology to support IND applications.
- Develop formulation strategies to improve drug delivery and bioavailability.
Our Advantages
Be it aid in small molecule drug design and development or any other area of research relating to mitochondrial diseases, our staff is prepared to provide exact help and tailored solutions that will solve your problems. If you are interested in availing our services, please feel free to contact us.
References
- Russell, O. M.; et al. (2020). Mitochondrial Diseases: Hope for the Future. Cell, 181(1), 168–188.
- Meng, L., & Wu, G. (2023). Recent advances in small molecules for improving mitochondrial disorders. RSC advances, 13(30), 20476–20485.
