An Improved Brain-Penetrating Nanoformulation of the VIPR2 Antagonist Peptide KS-133 for Treating Cognitive Impairment in Schizophrenia.
KS-133, a VIPR2 antagonist peptide, just got a serious upgrade for brain delivery. Researchers in Japan have developed a new nanoformulation that gets KS-133 across the blood-brain barrier more efficiently, aiming to tackle cognitive impairment in schizophrenia models.
Biol Pharm Bull
by Sakamoto K, Jin Z, Koan D et al.
“An Improved Brain-Penetrating Nanoformulation of the VIPR2 Antagonist Peptide KS-133 for Treating Cognitive Impairment in Schizophrenia. Sakamoto K(1), Jin Z(2)(3), Koan D(2)(4), Fujimoto R(1), Yokoyama R(2), Asano S(2), Ishimura R(5), Nunomura K(5), Lin B(5), Sugiyama D(6), Shiba H(4), Nishizawa N(7), Nakagawa S(3)(5)(8), Ago Y(2)(8). Author information: (1)Research & Development Department, Ichimaru Pharcos Co., Ltd., 318-1 Asagi, Motosu, Gifu 501-0475, Japan. (2)Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. (3)Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Osaka, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. (4)Department of Biological Endodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. (5)Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Sciences, The University of Osaka, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. (6)Translational Research Center, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. (7)Chemical Research Laboratories, Nissan Chemical Corporation, 2-10-1 Tsuboi-Nishi, Funabashi, Chiba 274-8507, Japan. (8)Global Center for Medical Engineering and Informatics, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. In 2024, we reported a brain-penetrant formulation of the vasoactive intestinal peptide receptor 2 (VIPR2) antagonist peptide KS-133 that mitigated cognitive dysfunction in the VIPR2 hyperactivation mouse model of schizophrenia. In this formulation, KS-133 was encapsulated in the hydrophobic core of nanoparticles (NPs) coated with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-KS-487 (DPPE-KS-487), a conjugate of the cyclic peptide KS-487 and DPPE produced by a click reaction that binds low-density lipoprotein-related protein 1, enabling blood-brain barrier penetration upon subcutaneous injection. However, the click reaction generated multiple positional isomers and manufacturing required repetitive cycles of ultrasonication at high and low temperatures, posing challenges for industrial scalability. In the current study, we coated KS-133-containing NPs with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-KS-487 (DSPE-KS-487), a novel conjugate of KS-487 with DSPE produced through a non-click method, thus eliminating positional isomers, and also established a simplified manufacturing process allowing a unidirectional transition from ultrasonication at high to low temperatures. This formulation remained physically and chemically stable for at least 12 months under refrigeration, with no changes in particle size, zeta potential, KS-133 content, or KS-487 presentation level. The formulation also exhibited brain penetration and therapeutic efficacy against VIPR2 agonist-induced novel object recognition impairment in mice comparable to those of DPPE-KS-487 NPs. Furthermore, no systemic side effects of hematologic, brain, heart, liver, and lung toxicity were detected following daily injections to mice for two weeks at five times the effective dose. This new KS-133 formulation incorporating DSPE-KS-487 as a brain-penetrant shuttle is a promising drug candidate for the treatment of cognitive dysfunction in schizophrenia.”
The previous version used a “click reaction” to coat KS-133 nanoparticles with a brain-targeting shell. That method worked, but the manufacturing was messy: it created a mix of isomers and required complex temperature cycling. Not ideal if you want to scale up or keep things consistent batch-to-batch.
Now, the team switched gears. They ditched the click chemistry and used a non-click method to attach KS-487 (the targeting peptide) to DSPE, creating DSPE-KS-487. The result: a clean, single-isomer coating that simplifies the whole process. Researchers can now manufacture these nanoparticles in a single, streamlined step.
Why does this matter for anyone interested in peptide research?
The new formulation stays stable for at least a year in the fridge. No loss of peptide, no weird aggregation, no change in size.
It delivers KS-133 to the brain just as effectively as the old version—demonstrated in mice with schizophrenia-like symptoms.
Mice tolerated high, repeated doses without any signs of systemic toxicity.
Key takeaway: Peptide nanoformulation is moving forward, and scalable, brain-penetrant delivery systems are now a reality for research compounds like KS-133. This is a win for anyone working on peptides targeting the central nervous system.
Want to keep up with breakthroughs like this? Check out the peptide research index for more updates on cutting-edge delivery tech and formulations. Peptide research is getting more robust—and a lot more interesting.
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