FOXO4-DRI (Proxofim) (10mg)

What is the FOXO4-DRI peptide?

FOXO4-DRI is a synthetic version of FOXO4, containing D amino acids instead of L amino acids. This modification is intended to allow the peptide to retain the functionality of the original protein with a longer shelf life and lower clearance from the body. Its most prominent function is suggested to be the regulation of apoptosis in senescent cells^[1]. It appears to inhibit FOXO4-p53 binding, thereby p53 may target pro-apoptotic genes and promote their expression. These proteins, in turn, may bring about apoptosis of old cells, thereby reducing the old cell burden in tissues. This increases cellular differentiation, tissue repair, and regrowth and decreases “biological age.” FOXO4 protein is a prominent member of the group of transcription factors that have the potential to regulate growth and differentiation. It is abundant in tissues such as the placenta, ovaries, fat cells, testes, and adrenal glands. Post-translational modifications, especially those in the DNA binding domain of FOXO4 protein, appear to modify its functionality as a transcription factor and regulation of pathways such as apoptosis, cellular senescence, insulin signaling, and senescence. FOXO4-D-Retro-Inverso is a synthetic ad partially altered form of the original FOXO4 protein. The modification was developed to help enhance the half-life of the protein and allows it to obstruct the normal FOXO4 function. FOXO4-DRI has been suggested to prevent normal FOXO4 binding to p53, eliminating of senescent cells, enhancing organ function, and reducing “biological age.” FOXO4-DRI appears to influence insulin signaling, cell cycle regulation, and oxidative stress signaling pathways. The peptide appears to be permeable into cells and has been suggested by researchers to selectively induce senescent cell apoptosis, thereby reversing aging effects in animal studies.

Specifications

AKA: Forkhead box protein O4, Proxofim, FOXO4a, AFX, AFX1, MLLT7

Sequence: H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH

Molecular Formula: C228H388N86O64

Molecular Weight: 5358.05 g/mol

Reconstitution: Required

What are DRI (D–Retro-Inverso) peptides?

DRI peptides are synthetic variants of their natural counterparts. The synthetic alternatives have the sequence of amino acids reversed as well as the alpha chirality changed^[2]. Naturally occurring amino acids have L chiral configuration, while the DRI peptides appear to be composed of D chiral amino acids. This has the potential to protect the synthetic peptides from enzymatic degradation and longer bioavailability. This leads to prolonged functional viability. They are also potential candidates for peptidomimetics for the study of protein-protein, protein-peptide, and peptide-peptide interactions. Biopharmaceuticals also prefer D peptides due to their apparent resistance to degradation, longer bioavailability, and low immunogenicity compared to their L counterparts.

FOXO4-DRI and Research in Aging, Senescence
FOXO4 is suggested to help the perpetuation of aged or senescent cells. It appears to bind to p53 and thereby may prevent apoptotic death of the senescent cells^[3]. The DRI peptide appears to prevent FOXO4-p53 interaction, thus p53 may activate apoptotic protein and induce cellular death. Thus the old cells may be cleared from tissues, naturally allowing for better tissue regeneration. Studies have observed treatment of aging mice with the DRI peptide has improved tissue regeneration and healthspan. Healthspan refers to the tenure of lifespan wherein the body remains active. It decreases with age. Tissue renewal can certainly reduce the biological aging of tissues and thereby enhance the health span of an individual. The aged mice exhibited a longer healthy life span, greater physical activity, lesser observed disability such as cardiac diseases and musculoskeletal dysfunction, etc.

FOXO4-DRI and Research in Insulin Signal Regulation
FOXO proteins are suggested to regulate the influence of insulin signaling and insulin-like growth factors. Scientific evidence suggests that the FOXO family of proteins act downstream of insulin signaling to regulate cellular growth, metabolism, differentiation, and oxidative stress. Mutations in FOXO genes have been suggested to cause diabetic toxicity such as hyperglycemia and hyperlipidemia and even lead to cancer. In the context of diabetes, it may lead to heart attack, impaired wound healing, stroke, and kidney damage, to name a few. Targeting FOXO signaling in the milieu of diabetes may lead to effective and targeted treatment regimens without any disease complications^[4]. The exact mechanism of FOXO4-DRI signaling is yet unknown. It is opined to reduce fasting blood sugar levels, thereby controlling diabetes.

FOXO4-DRI and Research in Heart Disease
Age is one of the critical factors which influence the onset of cardiac disease. The reason has been ascribed to loss of proteasome activity with age. Proteasome helps in the degradation of oxidized, modified, or damaged proteins, thereby keeping the cellular environment healthy. Reduction in proteasome functionality leads to the accumulation of toxic protein, which can be detrimental to cardiac tissues^[5]. FOXO signaling appears to have the potential to increase autophagy and proteasomal activity in the heart, clearing out damaged cells. It is thought that FOXO4-DRI protein or any variant of it may promote proteasomal functions, enhancing the health of cardiac tissues and reducing the risk of cardiovascular disease.

FOXO4-DRI and Research in Neurodegenerative diseases
The complex etiology of neurodegenerative diseases is yet to be completely understood. There is evidence that indicates the alteration in FOXO proteins to be a contributor to the disease etiology^[6]. A decrease in proteasomal activity enhances the underlying condition of Huntington’s disease, Alzheimer’s disease, Parkinson’s, and Prion disease. Hence, FOXO-DRI protein or other modified alternatives may be valuable in treating the conditions by substituting for the absence of native FOXO proteins.

Conclusion
The synthetic peptide thus holds a lot of promise concerning a stable alternative to indigenous FOXO4 protein. The composition appears to allow it to retain the functionality of the original protein while overcoming the enzymatic degradation. Thus its bioavailability appears to be enhanced with sustained physiological effects. More extensive and dedicated research has the potential to unravel the precise mechanism of the FOXO4-DRI protein in disease biology and amelioration such as diabetes, cancer, Alzheimer’s, Parkinson’s, cardiac disease, dementia, and cellular senescence. At present, the peptide is available only for animal experiments, and human consumption has not been approved. The modified protein FOXO4-DRI has been reported by researchers to exhibit excellent subcutaneous and low oral bioavailability in mice where it is administered.

References