Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with carboxypeptidase activity that was identified using our genomics platform. We implemented a rational design approach to identify potent and selective ACE2 inhibitors. To this end, picomolar inhibitors of ACE2 were designed and synthesized.

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β-Cyclodextrin (β-CD)-ended linear poly(N-isopropylacrylamide) (β-CD-PNIPAM) and Frech et-type benzyl ether dendron with an azobenzene group (Gx-Azo) at the apex site form noncovalently connected amphiphiles (NCCAs) by inclusion complexation between the azo group and β-CD. The NCCAs self-assemble into vesicles in water. Optical switching of the assembly and disassembly is realized by alternating visible and UV irradiation, which causes the isomerization of the azo groups and their consequent complexation and decomplexation with β-CD. The structure and morphology of the vesicles were characterized by dynamic light scattering (DLS), static light scattering (SLS), SEM, TEM, and AFM. These photoresponsive vesicles can further respond to heat stimuli resulting in reversible aggregation and disaggregation of the vesicles.

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Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.

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