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These properties underpin its potential for use as a drug design scaffold, especially for the treatment of cancer; indeed, several analogs of CTX have reached clinical trials. Here, we focus on its ability to internalize into cells\u2014a trait associated with a privileged subclass of peptides called cell\u2010penetrating peptides\u2014and whether it can be improved through conservative substitutions. Mutants of CTX were made using solid\u2010phase peptide synthesis and internalization into human cervical carcinoma (HeLa) cells was monitored by fluorescence and confocal microscopy. CTX_M1 (ie, [K15R\/K23R]CTX) and CTX_M2 (ie, [K15R\/K23R\/Y29W]CTX) mutants showed at least a twofold improvement in uptake compared to CTX. We further showed that these mutants internalize into HeLa cells largely via an energy\u2010dependent mechanism. Importantly, the mutants have high stability, remaining intact in serum for over 24\u00a0h; thus, retaining the characteristic stability of their parent peptide. Overall, we have shown that simple conservative substitutions can enhance the cellular uptake of CTX, suggesting that such type of mutations might be useful for improving uptake of other peptide toxins.\n                  <\/jats:p>","DOI":"10.1002\/bip.23025","type":"journal-article","created":{"date-parts":[[2017,5,1]],"date-time":"2017-05-01T02:59:15Z","timestamp":1493607555000},"source":"Crossref","is-referenced-by-count":13,"title":["Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake"],"prefix":"10.1002","volume":"108","author":[{"given":"Paola G.","family":"Ojeda","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland Brisbane QLD 4072 Australia"},{"name":"Centro de Bioinform\u00e1tica y Simulaci\u00f3n Molecular (CBSM) Universidad de Talca Talca Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f3nia 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