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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
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Fc-GDF15 glyco-engineering and receptor binding affinity optimization for body weight regulation.

Ella Fung1, Liya Kang2, Diana Sapashnik1

  • 1BioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.

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|April 27, 2021
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Summary

Engineered Growth Differentiation Factor 15 (GDF15) as an Fc-fusion protein shows promise for treating obesity. This novel format improves therapeutic properties, enhancing efficacy and manufacturability for metabolic diseases.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Growth Differentiation Factor 15 (GDF15), a TGF-β family member, induces anorexia and weight loss, making it a potential therapeutic target for obesity and metabolic diseases.
  • Current GDF15 therapeutic development faces challenges due to its short half-life, aggregation tendency, and protease susceptibility.

Purpose of the Study:

  • To engineer GDF15 into an Fc-fusion protein format to improve its pharmacokinetic and physicochemical properties for therapeutic applications.
  • To enhance GDF15's efficacy and develop a more manufacturable therapeutic for obesity and associated metabolic disorders.

Main Methods:

  • Structure-based engineering combining knob-into-hole Fc technology and N-linked glycosylation site mutagenesis for half-life extension, solubility, and protease resistance.
  • Identification of GDF15 mutations at the receptor binding site to increase GFRAL binding affinity and half-life.
  • Single point mutation identification to enhance p-ERK signaling activity for improved weight loss efficacy.

Main Results:

  • Developed an Fc-fusion protein format of GDF15 with extended half-life, improved solubility, and enhanced protease resistance.
  • Identified mutations increasing GFRAL binding affinity, leading to significant half-life extension.
  • A specific mutation demonstrated increased p-ERK signaling and improved in vivo weight loss efficacy.

Conclusions:

  • The engineered GDF15 Fc-fusion protein exhibits improved therapeutic properties, including enhanced efficacy and potential for better manufacturability.
  • This novel format addresses key challenges in developing GDF15 as a viable therapeutic for obesity and metabolic diseases.