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Through the l - to d - type amino acid substitution and attachment of solubilizing tags, the novel proteolysis-resistant and water-soluble fluorescent probes were developed, which could achieve the sensitive "turn on" sensing of heparin. [Display omitted] • The first systematic structural optimizations were conducted on the promising fluorescent probe TPE-1 for heparin sensing. • The novel d -type peptide based fluorescent probes were developed for the highly sensitive "turn on" sensing of heparin. • The representative heparin probe XH-6 was demonstrated to possess extremely high proteolytic stability and good solubility. Developing "turn on" fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising "turn on" fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based "turn on" probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d -type peptide fluorescent probe XH-6 indicated that d -type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of "turn on" fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d -type peptides based fluorescent probes. [ABSTRACT FROM AUTHOR]