en.Wedoany.com Reported - The team led by Xu Huaqiang and Li Jia from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, drawing inspiration from the human body's physiological rhythms, has proposed a "first principle" for drug design and innovated the "pulsatile activation" drug development concept. Based on this, they have developed a new candidate drug for chronic liver disease, Linafexor (CS0159). The achievement was published in the international journal Nature on June 10.
Bile acids are secreted by liver cells and are responsible for the digestion and absorption of fats. Bile acid receptors, acting as the "master switch" for bile acids, are key drug targets for treating various major liver diseases. However, current related drugs worldwide generally face significant clinical limitations such as pronounced side effects, making the development of safer new drugs an urgent challenge for the industry.
In a healthy human body, bile acid levels briefly rise after meals and rapidly decline during fasting, exhibiting a "relaxation-contraction" pulsatile pattern. Traditional drug design concepts often pursue "continuous activation, the stronger the better" of bile acid receptors, which is equivalent to "holding down the switch" and violates the body's normal physiological rhythm.
The research team broke away from the traditional development framework and proposed a "first principle" for drug design centered on "dynamic physiological homeostasis." Li Jia explained that an ideal drug should follow normal physiological rhythms, with its essence lying in returning to nature and restoring the body's dynamic balance. Accordingly, the team designed the molecule CS0159, which can "enter and exit quickly" in the human body. It briefly activates bile acid receptors, mimicking the fluctuating rhythm of natural bile acids, thereby preventing receptor failure due to long-term overexertion. At the same time, the molecule is rapidly metabolized and cleared, fundamentally avoiding the side effects associated with long-term use. Phase II clinical trial data confirmed that the drug demonstrates excellent performance in both efficacy and safety.
"Physiological mechanisms such as hormone secretion, immune regulation, and circadian metabolism in the human body are all regulated by rhythmic signals. The 'pulsatile activation' concept can provide methodological support for innovative drug development, reducing risks and improving the efficiency of drug development," said Xu Huaqiang. Currently, the drug has initiated Phase III clinical studies and is expected to offer a new treatment option for patients with liver diseases caused by bile acid metabolism disorders.
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