Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity.

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator shown to improve glycemic control. However, the molecular and functional mechanisms underlying FGF21-mediated improvements in glycemic control are not completely understood. We examined FGF21 effects on insulin sensitivity and glucose fluxes upon chronic (daily injection for 8 d) and acute (6 h infusion) administration in ob/+ and ob/ob mice.

FGF21: a novel prospect for the treatment of metabolic diseases.

The increasing prevalence of metabolic diseases is alarming and highlights the need for more effective and safer therapies to treat these diseases. Recent evidence from several animal studies indicates that FGF21 induces numerous beneficial metabolic changes without apparent adverse effects. These results suggest that FGF21 could be a novel and attractive drug candidate for the treatment of cardiovascular disease, obesity and type 2 diabetes.

Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases.

Fibroblast growth factor (FGF)-21 is a unique member of the FGF family, with several molecular characteristics that differ from classical FGFs and exhibiting a pharmacologic profile that includes a variety of metabolic responses in vitro and when tested in vivo in animal models. FGF21 represents a novel and attractive therapeutic agent for type 2 diabetes mellitus, because of its ability to modulate disease phenotype in preclinical settings without inducing any apparent adverse effects. Although FGF21 was discovered relatively recently, the understanding of its biology and therapeutic utility is rapidly evolving.

FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho.

Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that betaKlotho is an integral part of an activated FGF-21-betaKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking betaKlotho did not respond to FGF-21; the introduction of betaKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells.

The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21.

Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents. Importantly, these effects were durable and did not come at the expense of weight gain, hypoglycemia, or mitogenicity.

Enhancing exposure of protein therapeutics.

Therapeutic proteins have made a major impact on medicine, with significant expansion in the past two decades. The medicinal attributes of these agents, particularly their efficacy and often their safety profile, make protein therapeutics attractive, despite the general necessity of invasive (parenteral) delivery. This perceived hurdle has been a primary component in limiting expansion of this class of drug therapies.

Engineering of recombinant antibody fragments to methamphetamine by anchored periplasmic expression.

The detection of methamphetamine and other chemically related illicit drugs relies extensively on immunoassays. Here we report the cloning and affinity maturation of an anti-methamphetamine antibody which is being employed in the current commercial assays. An anti-methamphetamine scFv was cloned from hybridoma cells, expressed in bacteria and its affinity towards methamphetamine and N-ethylamphetamine (ethamphetamine) was determined by Surface Plasmon Resonance (SPR).

FGF-21 as a novel metabolic regulator.

Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity.

Diversity in hapten recognition: structural study of an anti-cocaine antibody M82G2.

Antibodies against cocaine and other drugs of abuse are the basis for diagnostic tests for the presence of those drugs in human serum. The 1.7A resolution crystal structure of the anti-cocaine monoclonal antibody M82G2 in complex with cocaine is presented.

Medicinally useful proteins--enhancing the probability of technical success in the clinic.

Proteins that are normally present in organisms function to maintain the overall homeostatic balance of the living system. Although an understanding of the biology of these proteins is essential to determining their utility in the treatment of disease, the administration of wild-type forms of proteins in a therapeutic manner (often systemically and at concentrations much higher than those found in the healthy organism) can have the effect of inappropriate activation of cell types and compartments that can lead to an undesirable response. Modification of the sequence of the parent protein to yield selected biological properties can generate derivative versions (muteins) having an optimal therapeutic profile.

Anchoring a cationic ligand: the structure of the Fab fragment of the anti-morphine antibody 9B1 and its complex with morphine.

The crystal structures of an anti-morphine antibody 9B1 (to 1.6A resolution) and its complex with morphine (to 2.0 A resolution) are reported.

Generation of highly selective VPAC2 receptor agonists by high throughput mutagenesis of vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide.

Pituitary adenylate cyclase-activating peptide (PACAP) has a specific receptor PAC1 and shares two receptors VPAC1 and VPAC2 with vasoactive intestinal peptide (VIP). VPAC2 activation enhances glucose-induced insulin release while VPAC1 activation elevates glucose output. To generate a large pool of VPAC2 selective agonists for the treatment of type 2 diabetes, structure-activity relationship studies were performed on PACAP, VIP, and a VPAC2 selective VIP analog.

Therapeutic enhancement of IL-2 through molecular design.

A recombinant human IL-2 analog (rIL-2, Proleukin) is currently being evaluated for clinical benefit in HIV infected patients. It is approved for therapy of patients with metastatic melanoma and renal cell carcinoma. Treatment of cancer patients with rIL-2 results in durable responses but is associated with life-threatening toxicity, which limits its use to patients in relatively good health.