The melanocortin peptide therapeutic setmelanotide, (ImcivreeTM), is highly effective in the treatment of the rare obesity syndromes, POMC and leptin receptor deficiency. However, the drug is ineffective for the most common syndromic obesity, melanocortin-4 receptor (MC4R) deficiency (MC4R haploinsufficiency), found at a prevalence greater than 1/1000 individuals. Further, the drug is ineffective in the treatment of dietary obesity. In addition to the fact that Imcivree does not address the unmet medical needs in patients with syndromic obesity due to MC4R deficiency, Imcivree is a pan-agonist of four melanocortin receptors and causes hyperpigmentation by activating the melanocortin-1 receptor (MC1R) on dermal and follicular melanocytes. Lastly, the formulation of Imcivree is not ideal, requiring daily subcutaneous administration. In our Phase I application, we proposed to develop melanocortin-3 receptor antagonists as peptide therapeutics for MC4R deficiency, since the MC3R is a negative regulator of MC4R neurons. However, in the course of developing these molecules, currently still in progress, we made a striking discovery. Based on the extensive structure-activity relationship (SAR) work initiated in Phase 1, we also identified four novel families of MC4R agonists. Characterizing select peptides in a validated obese mouse model of human MC4R deficiency (MC4R+/- mice), we discovered two families of these MC4R agonist peptides that, unlike Imcivree, have significant weight loss efficacy in MC4R haploinsufficiency, as well as in dietary obesity. More recent work provides modified versions of these peptides that have reduced MC1R efficacy as well. Finally, we have shown that melanocortin peptides can be formulated in injectable PLGA microspheres by a new remote-loading technique, yielding steady release of peptide for more than 30 days offering the potential for optimizing the therapeutic window, improving patient compliance, and reducing cost. In this phase II application, we propose to 1) complete the chemical development of MC4R agonist peptides for the treatment of MC4R deficiency, 2) complete pre-GLP safety studies for up to three peptide development candidates for MC4R deficiency, and 3) formulate and characterize the pharmacokinetics, efficacy, and side effect profile of these peptides in our mouse model of human MC4R deficiency. The product of this Phase II STTR proposal will be one or more therapeutic candidates for the treatment of MC4R haploinsufficiency, and a pathway to commercialization of these therapeutics.