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The marine\u2010derived cyclic heptapeptide stylissatin A (SA) and its analog\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Tyr\n                    <jats:sup>1<\/jats:sup>\n                    (\n                    <jats:italic>t<\/jats:italic>\n                    Bu)\u2010SA (\n                    <jats:bold>1<\/jats:bold>\n                    ) localize to lysosomes and inhibit the interaction between the protective protein cathepsin A (PPCA) and neuraminidase\n                    <jats:bold>1<\/jats:bold>\n                    (Neu1), thereby promoting lipid droplet degradation and suppressing fat accumulation. To improve cellular uptake and therapeutic efficacy, we introduced\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylation into the macrocyclic backbone of\n                    <jats:bold>1<\/jats:bold>\n                    and synthesized a new analog,\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Tyr\n                    <jats:sup>1<\/jats:sup>\n                    (\n                    <jats:italic>t<\/jats:italic>\n                    Bu)\u2010\n                    <jats:italic>N\u2010<\/jats:italic>\n                    Me\u2010Ile\n                    <jats:sup>4<\/jats:sup>\n                    \u2010SA (\n                    <jats:bold>2<\/jats:bold>\n                    ), via solid\u2010phase peptide synthesis followed by solution\u2010phase macrocyclization.\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylation at Ile\n                    <jats:sup>4<\/jats:sup>\n                    induced a marked conformational change from\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010Pro\n                    <jats:sup>3<\/jats:sup>\n                    to\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010Pro\n                    <jats:sup>3<\/jats:sup>\n                    and increased conformational flexibility in solution. Upon binding to PPCA, this flexibility triggered a transition at Pro\n                    <jats:sup>5<\/jats:sup>\n                    from\n                    <jats:italic>trans<\/jats:italic>\n                    to\n                    <jats:italic>cis<\/jats:italic>\n                    . The enhanced hydrophobicity further promoted favorable interactions within the binding pocket. Consequently,\n                    <jats:bold>2<\/jats:bold>\n                    exhibited improved anti\u2010inflammatory and similar anti\u2010adipogenic activities compared to\n                    <jats:bold>1<\/jats:bold>\n                    . Furthermore, the biotin analog of\n                    <jats:bold>2<\/jats:bold>\n                    exhibited a higher binding affinity to activated PPCA with a\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    value 29\u2010fold smaller than that of\n                    <jats:bold>1<\/jats:bold>\n                    , demonstrating the functional advantage of backbone\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylation. This PPCA\u2013Neu1 interaction\u2010inhibitory mechanism differs from that of glucagon\u2010like peptide\u20101 (GLP\u20101) receptor agonists, highlighting a distinct intracellular therapeutic strategy for the development of next\u2010generation anti\u2010obesity agents.\n                  <\/jats:p>","DOI":"10.1002\/asia.70906","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T06:50:41Z","timestamp":1785048641000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Backbone\n                    <i>N<\/i>\n                    \u2010Methylation Improves PPCA\u2010Binding of a Stylissatin A Analogue via Conformational Modulation"],"prefix":"10.1002","volume":"21","author":[{"given":"Dewi","family":"Luthfiana","sequence":"first","affiliation":[{"name":"Department of Applied Biosciences, Graduate School of Bioagricultural Sciences Nagoya University, Furo\u2010cho, Chikusa  Nagoya 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