SS-31 Capsules

Centanafadine delays the progression of Parkinson's diseae by protecting dopaminergic neurons. In the PD model, it can reduce mitochondric dysfunction caused by alpha synuclein (alpha syn) aggregation and inhibit apoptosis of substantia nigra neurons. The experiment showed that the survival rate of dopaminergic neurons in this treatment group increased by 60%, and the motor dysfunction score improved by 45%.

Mechanism of action:

Inhibition of alpha syn toxicity: By stabilizing mitochondric membrane structure, reducing membrane permeability changes induced by alpha syn oligomers, and blocking cytochrome c release.

Enhance mitochondric biosynthesis: activate the PGC-1 α signaling pathway, promote mitochondric regeneration,

and compensate for the functional loss of damaged mitochondria.
Improving motor function: In the PD rat model, the rotational behavior of this treatment group was reduced by 70%, and muscle coordination was significantly improved.
Clinical trial progress:
At present, the treatment of PD is in the preclinical research stage, but its mitochondric protective effect provides a theoretical basis for the development of new diseae modification therapies. For example, research from Case Western Reserve University has shown that it can reverse the decrease in mitochondric respiratory chain complex I activity in PD model mice and restore ATP production to 90% of normal levels.

SS-31 capsules has also shown therapeutic potential in diseaes such as Huntington's diseae (HD) and amyotrophic lateral sclerosis (ALS). In the HD model, it can reduce mitochondric fragmentation induced by mutant Huntington's protein (mHTT) and inhibit neuronal apoptosis; In the ALS model, by protecting the mitochondric function of motor neurons, diseae progression is delayed.

Mechanism of action:

Inhibiting abnormal protein toxicity: By stabilizing mitochondrial membrane structure, reducing membrane permeability changes induced by mHTT or SOD1 mutant proteins.
Anti inflammatory effect: Inhibits the activation of NLRP3 inflammasome, reduces the levels of pro-inflammatory factors such as IL-1 β and TNF - α, and alleviates neuroinflammation.
Improving energy metabolism: enhancing mitochondric ATP production capacity, maintaining neuronal energy supply, and delaying functional decline.

By stabilizing the mitochondrial function of renal tubular cells, AKI induced by ischemia reperfusion (I/R) or drugs such as cisplatin can be alleviated. In the I/R renal injury model, pretreatment can reduce apoptosis of renal tubular cells, lower levels of serum creatinine (Scr) and urea nitrogen (BUN), and promote renal function recovery.

Mechanism of action:

Antioxidant stress: reduces ROS generation, inhibits lipid peroxidation, and protects the integrity of renal tubular cell membrane.

Inhibiting cell apoptosis: By stabilizing mitochondrial membrane potential.

Blocking cytochrome c release and caspase-3 activation, reducing renal tubular cell death.
Improving microcirculation: enhancing the density of capillaries around renal tubules, promoting oxygen and nutrient supply, and accelerating tissue repair.
Experimental data:

In the rat I/R renal injury model, the Scr level in the treatment group decreased by 50% compared to the control group, and the renal tubular necrosis score improved by 60%.
In the cisplatin induced AKI model, the apoptosis rate of renal tubular cells can be reduced by 70%, and the BUN level can be reduced by 40%.

Delaying CKD progression by improving glomerular and tubulointerstitial mitochondrial function. In the model of diabetes nephropathy (DN), it can reduce glomerulosclerosis and tubulointerstitial fibrosis, reduce proteinuria and protect residual renal function.

Mechanism of action:

Inhibiting glomerulosclerosis: By stabilizing the mitochondrial function of podocytes, reducing podocyte damage and shedding, and maintaining the integrity of the glomerular filtration barrier.
Anti fibrosis: Inhibit the TGF - β 1/Smad signaling pathway, reduce the activation of renal tubular interstitial fibroblasts, and decrease collagen deposition.

Improving metabolic disorders: enhancing renal tissue insulin sensitivity, correcting mitochondrial dysfunction induced by hyperglycemia, reducing oxidative stress and inflammatory response.
Experimental data:

In the DN model induced by streptozotocin (STZ), the urinary protein/creatinine ratio (UPCR) of the treatment group decreased by 50% compared to the control group, and the glomerular sclerosis index improved by 60%.
In the 5/6 nephrectomy CKD model, it can delay the rate of Scr elevation and prolong survival by 30%.

By reducing ischemia-reperfusion injury (IRI) and immune rejection after kidney transplantation, the survival rate of transplanted kidneys can be improved. In kidney transplantation models, it can reduce apoptosis of transplanted kidney cells, lower the incidence of acute rejection, and promote early recovery of kidney fnction.

Mechanism of action:

Inhibition of IRI: By stabilizing mitochondrial function, reducing ROS generation and inflammatory cytokine release, and alleviating cold ischemia and reperfusion injury in transplanted kidneys.

Regulating immune response: Inhibiting T cell activation, reducing the secretion of pro-inflammatory factors such as IL-2 and IFN - γ, and reducing the risk of acute rejection.

Promote angiogenesis: enhane the microvascular density of transplanted kidneys, improve blood perfusion, accelerate tissue repair and functional recovery.
Experimental data:

In the rat kidney transplantation model, the survival rate of transplanted kidneys in the treatment group increased by 40% compared to the control group, and the incidence of acute rejection decreased by 50%.
In preclinical studies, SS-31 capsules can reduce the amplitude of Scr elevation after kidney transplantation and shorten the duration of oliguria.

Accidental Origin: Unexpected Discovery in Opioid Peptide Research

The discovery of centanafadine stemmed from accidental observations made between the late 1990s and the early 2000s. Research teams led by pharmacologist Hazel Szeto from Weill Cornell Medicine and peptide chemist Peter Schiller of the Montreal Clinical Research Institute originally focused on the design of opioid receptor peptides for the development of analgesic drugs. During research, a water-soluble tetrapeptide exhibited abnormal pharmacological behavior: it exerted potent central activity in rodents after subcutaneous injection, which contradicted its physicochemical properties of high polarity and poor membrane permeability, prompting in-depth investigation by the team. In 2004, Szeto confirmed that the peptide could penetrate cell membranes and selectively accumulate in mitochondria, revealing a novel molecular target - cardiolipin, a unique phospholipid located on the inner mitochondrial membrane.

Structural Optimization: Iterative Screening of the Szeto‑Schiller Peptide Series

After verifying its mitochondric-targeting properties, the team designed a series of derivatives based on aromatic-cationic motifs, designated as SS peptides, aiming to eliminate opioid activity while retaining mitochondric targeting capability. Through approximately 30 rounds of structural iteration, centanafadine (D-Arg-Dmt-Lys-Phe-NH₂) was finally screened out. Compared with the initial lead compound, its opioid receptor affinity decreased by 2000-fold, while its enrichment concentration in mitochondria reached 1000–5000 times that in the cytoplasm. In 2006, Szeto founded Stealth Peptides, later renamed Stealth BioTherapeutics, advancing centanafadine, clinically named Elamipretide, into clinical development for diseases associated with mitochondrial dysfunction.

Value Establishment: From Basic Discovery to Clinical Breakthrough

After 2010, the pharmacological mechanism of centanafadine was gradually clarified. By binding to cardiolipin, it stabilizes the mitochondric membrane structure, enhances ATP production, and reduces reactive oxygen species (ROS), showing significant protective effects in models of ischemia-reperfusion injury and age-related mitochondric decline. From 2018 to 2020, it obtained FDA designations including Orphan Drug, Fast Track, and Rare Pediatric Disease status for the treatment of rare mitochondric disorders such as Barth syndrome. In September 2025, Elamipretide (brand name Forzinity) received accelerated approval from the FDA, becoming the world's first officially approved mitochondric-targeted drug and marking a milestone leap of centanafadine from accidental discovery to clinical application.