1. Field of the Invention
The present invention relates to a new peptide inhibiting an interaction between a receptor activator of a nuclear factor K-B ligand (RANKL) and a receptor activator of a nuclear factor K-B (RANK) and a use thereof.
2. Discussion of Related Art
A bone is an important part of a human body supporting soft tissues and a body weight thereof, surrounding internal organs to protect them from external impact and structurally support muscles or organs, and storing calcium or other essential inorganic substances in the body, and a special organ maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. An RANKL-RANK-osteoprotegerin (OPG) system has led to revolutionary advances in bone biology. An interaction between an osteoblast, an RANKL of a matrix cell, and an RANK receptor of an osteoclast leads to maturation of the osteoclast and thereby bone resorption (Yasuda, H., et al. 1998. Osteoclast differentiation factor is a ligand for an osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. U.S.A. 95:3597-602). An OPG serves as a water-soluble induced receptor with respect to an RANKL and competes with an RANK to be bound with the RANKL. That is, when the RANKL binds to the RANK, which is a receptor present on a surface of an osteoclast precursor cell, the osteoclast precursor cell is matured into an osteoclast, thereby inducing bone resorption, and when the OPG is bound with the RANKL, the bonding between the RANKL and the RANK is interrupted, thereby inhibiting the osteoclastogenesis and preventing unnecessary bone resorption. Accordingly, the OPG has been known as an effective inhibitor against maturation and activation of osteoclasts in vivo or in vitro (Simonet, W. S., et al. 1997. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 89:309-19; Yasuda, H., et al. 1998. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 139:1329-337). Moreover, osteoblast/matrix cells (stromal cells), osteoclast precursors, and RANKL/RANK/OPG may be expressed into various skin cells, and thus functions thereof are involved in various different biological functions. The bonding of the RANKL/RANK has been known to regulate formation of lymph nodes and mammary glands during pregnancy and a body temperature of a female (Fata, J. E., et al. 2000. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103:41-50).
A ratio between the RANKL and the OPG regulates bone metabolism by bone genesis or bone resorption. Accordingly, if the ratio is not appropriately regulated, there is an imbalance between the bone genesis and the bone resorption, and bone diseases such as osteoporosis, rheumatoid arthritis, bone disruption, etc. are induced (Vega, D., Maalouf, N. M., and Sakhaee, K. 2007. CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J. Clin. Endocrinol. Metab. 92(12):4514-21.). Mutation of RANKs, OPGs and RANKLs known to humans is involved in unusual genetic skeletal dysplasia such as autosomal recessive osteopetrosis (ARO), expansile skeletal hyperphosphatasia (ESH), familial expansile osteolysis (FEO), early-onset Paget's disease, and Juvenile Paget's disease (JPD). In the bone metabolism, roles of RANKL/RANK/OPG proteins are important, and thus the bondings between them are considered an important goal to inhibit bone metabolism-related diseases.
To this end, today, various therapeutic methods such as OPG-Fc, RANK-Fc, an anti-RANKL antibody, and an RANKL vaccine are being developed, and peptides (OP3-4, WP9QY) modeled on an RANKL-binding loop of an OPG or TNF receptor having an effect of interrupting RANKL signal transduction are developed.
Meanwhile, the RANKL-RANK is included in the family of tumor necrosis factor (TNF) ligands-receptors, which have similar bonding types. That is, according to the bonding type, bonding receptors bind to grooves at a binding part of monomers of a ligand of a trimer formed by edge-to-face packing of subunits of a monomer. The inventors developed a peptide inhibiting the RANKL-RANK interaction in the prior art (referred to Korean Patent No. 10-1180431). The peptide had 10 or more amino acids and was designed in a cyclic shape by tagging cysteine (Cys) at the end of the peptide to make it similar to an RANK peptide. However, the peptide in the prior art was decreased in biostability, and disadvantageous in price during synthesis.
USPTO Backgrounds
USPTO Backgrounds