Fibroblast growth factors (FGFs) regulate various developmental and metabolic processes, including cell proliferation, differentiation, angiogenesis, wound healing, nerve regeneration, chronic inflammation, and cancer growth. The FGF family consists of 22 members that share the β-trefoil fold despite their relatively low sequence identities (13–71%). The β-trefoil fold contains 12 β-strands that form 6 two-stranded β-hairpins (i.e., β1-β12, β2-β3, β4-β5, β6-β7, β8-β9, and β10-β11). Hairpins are arranged in a pseudo three-fold symmetry: the first, third, and fifth β-hairpins form a barrel that is covered by a triangular cap consisting of the second, fourth, and sixth β-hairpins.

FGFs are divided into FGF1, FGF4, FGF7, FGF8, FGF9, FGF11, and FGF19 subfamilies depending on their sequence similarities. Except for the intracellular FGF11 subfamily, FGFs form complexes with FGF receptors (FGFRs) on the cell membrane, which are generally composed of three immunoglobulin (Ig)-like extracellular domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. FGFs bind to the interface between the second and third Ig-like ectodomains to induce receptor dimerization, leading to the phosphorylation of tyrosine residues in the cytoplasmic domain to stimulate signaling pathways.

The canonical FGFs (FGF1, FGF4, FGF7, FGF8, and FGF9 subfamilies) have a positively charged sector clustered by lysine and arginine residues and thus display avidity for negatively charged heparin/heparan sulfate proteoglycans (HSPGs) present on the cell surface or in the extracellular matrix. Therefore, canonical FGFs form ternary complexes with HSPG and FGFR, and act in the vicinity of cells as paracrine and/or autocrine factors. Conversely, FGF19 subfamily members (FGF19, FGF21, and FGF23) have no apparent HSPG-binding site on their surfaces and thus perform their physiological roles in an endocrine manner. They are released from the extracellular matrix and reach remote target organs through the bloodstream.

Complex model structure of
FGFR1c/FGF21/KLB

DJ-1, which is extensively expressed in the testis and moderately in other tissues, was first identified as a novel candidate of the oncogene product that transformed mouse NIH3T3 cells in cooperation with activated ras. After the first identification, various physiological roles of DJ-1 have been unveiled. It has been shown that DJ-1 is a circulation tumor antigen in breast cancer, in which DJ-1 is secreted from cells to serum. DJ-1 was also characterized as a protein that regulates an RNA-protein interaction and positively modulates the androgen receptor (AR). Remarkably, the loss of function mutations in DJ-1 gene was revealed to be responsible for the autosomal recessive early-onset Parkinson’s disease (PD). Compatible with diverse cellular functions, human DJ-1 has at least three distinct biochemical activities: chaperon activity, protease activity, and glyoxalase activity.

Antibiotic resistance: β-Lactamases, that are classified into four classes (A, B, C and D) based on their amino acid sequences, inactivate β-lactam antibiotics. A proven strategy to counter resistance to β-lactam antibiotics is the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs). We have discovered marine natural-derived hit compounds that inhibit β-lactamases, addressing the current antibiotic resistance crisis. Developing antibiotics from these findings could lead to new BLIs with unique structures that could escape bacterial resistance mechanisms adapted to existing BLIs

Class C β-lactamase

& Antibiotics candidates