Minimalist d‑Tripeptide Prodrug Mimetics of the Myostatin Prodomain as Selective Inhibitors of Skeletal Muscle Atrophy Signaling

Skeletal muscle atrophy is driven in part by unrestrained myostatin (MSTN) signaling. We designed all-d tripeptide prodrug mimetics of the MSTN prodomain minimum active 23-mer fragment. Compounds 1 (H-d-Arg-d-Leu-d-Ala-OiPr) and 2 (H-d-Arg-d-Abu-d-Ala-OiPr) inhibited MSTN-induced myotube atrophy with sub-micromolar potency, while free-acid analogues (3, 4) and scrambled control (scr) were less active. All-d configuration conferred proteolytic stability exceeding 24 h. In vivo, compound 1 increased soleus mass and grip strength in mice. This work establishes compound 1 as a lead prodrug for MSTN antagonism in muscle atrophy.