Abstract The goal of this SBIR phase I is to develop new therapeutics for treatment of various iron overload diseases that involves the use of hepcidin mimetics and to identify an Investigational New Drug (IND) candidate that is effica- cious in the disease model of thalassemia. There are two predominant diseases, hemochromatosis and ?-tha- lassemia, that are characterized with iron overload. In both diseases low hepcidin levels increase intestinal iron absorption and increase release of recycled iron from the reticuloendothelial system which causes depletion of macrophage iron, relatively lower levels of serum ferritin, increase in liver iron concentration, and release into the circulation of free iron that causes target-organ damage. Without treatment, iron continues to accumulate, and a considerable proportion of patients eventually reach toxic iron-overload levels. Patients are treated by phlebotomy, blood transfusions and/or iron chelators depending on the disease. Chelation therapy is associated with considerable toxicity and currently existing chelators used for treating iron overload, lack significant patient compliance or are associated with toxicity, renal impairment, hepatic impairment, and gastrointestinal hemor- rhage. Thus, there is significant need for new treatments that are safer and better tolerated. Because of hepcidins complicated 4-disulfide structure, hepcidin mimetics have been proposed as a potential therapeutic. To over- come the physicochemical limitations of hepcidin, more potent, stable, soluble and efficacious alternate scaffolds than hepcidin were engineered by using a purposefully built structure-based drug environment (Vectrix?). A lead compound (PN-8518) was identified after optimizing and profiling engineered scaffolds identified by Vec- trix?. In this SBIR phase I we plan to: 1) synthesize and characterize 11 compounds with variable serum protein binding groups on a single position of PN-8518, 2) select the best two compounds in a PD model and 3) test the best two compounds in a PD model in diseased mice, and 4) test the best compound in a 6-week disease model, and finally 4) undertake a PK/PD study of the best compound to predict human dose. A strong scientific team and consultants experienced in the field of iron overload diseases and biological drug development will lead us to select a drug development candidate that can be taken into nonclinical safety studies and then Phase I clinical trials.