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In this study, we investigated the ability of aggrelyte\u20102 (N,S\u2010diacetyl\u2010L\u2010cysteine methyl ester) to reverse the water insolubility of aged human lens proteins and to decrease stiffness in cultured human and mouse lenses. Water\u2010insoluble proteins (WI) of aged human lenses (65\u201375\u2009years) were incubated with aggrelyte\u20102 (500\u2009\u03bcM) for 24 or 48\u2009h. A control compound that lacked the S\u2010acetyl group (aggrelyte\u20102C) was also tested. We observed 19%\u201330% solubility of WI upon treatment with aggrelyte\u20102. Aggrelyte\u20102C also increased protein solubility, but its effect was approximately 1.4\u2010fold lower than that of aggrelyte\u20102. The protein thiol contents were 1.9\u2010 to 4.9\u2010fold higher in the aggrelyte\u20102\u2010 and aggrelyte\u20102C\u2010treated samples than in the untreated samples. The LC\u2013MS\/MS results showed <jats:italic>N<\/jats:italic><jats:sup><jats:italic>\u03b5<\/jats:italic><\/jats:sup>\u2010acetyllysine (AcK) levels of 1.5 to 2.1\u00a0nmol\/mg protein and 0.6 to 0.9\u00a0nmol\/mg protein in the aggrelyte\u20102\u2010 and aggrelyte\u20102C\u2010treated samples. Mouse (C57BL\/6J) lenses (incubated for 24\u2009h) and human lenses (incubated for 72\u2009h) with 1.0\u2009mM aggrelyte\u20102 showed significant decreases in stiffness with simultaneous increases in soluble proteins (human lenses) and protein\u2010AcK levels, and such changes were not observed in aggrelyte\u20102C\u2010treated lenses. Mass spectrometry of the solubilized protein revealed AcK in all crystallins, but more was observed in \u03b1\u2010crystallins. These results suggest that aggrelyte\u20102 increases protein solubility and decreases lens stiffness through acetylation and disulfide reduction. Aggrelyte\u20102 might be useful in treating presbyopia in humans.<\/jats:p>","DOI":"10.1111\/acel.13797","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T04:25:30Z","timestamp":1677212730000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Aggrelyte\u20102 promotes protein solubility and decreases lens stiffness through lysine acetylation and disulfide reduction: Implications for treating presbyopia"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8413-2913","authenticated-orcid":false,"given":"Sudipta","family":"Panja","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, Sue Anschutz\u2010Rodgers Eye Center University of Colorado Anschutz Medical Campus  Colorado Aurora USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rooban 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