Amgen's Dual-Target GLP-1/GIP-Based Weight Loss and Glucose-Lowering Drug AMG 133 Granted Clinical Trial Approval in China

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Recently, Academician Wang Rui, Mu Lingyun, and Associate Professor Zhang Hailong from the School of Basic Medical Sciences, Lanzhou University/Gansu Provincial Key Laboratory of Preclinical Study for New Drugs, jointly published a research article titled "Microcolin H, a novel autophagy inducer, exerts potent antitumour activity by targeting PITPα/β" in the internationally renowned journal Signal Transduction and Targeted Therapy (IF=39.3). The study utilized a multidisciplinary collaborative strategy (natural product chemical synthesis—chemoproteomics target confirmation—anti-tumor mechanism investigation—activity evaluation) to systematically investigate how the marine peptide Microcolin H exerts powerful anti-tumor activity by directly targeting PITPα/β to induce autophagy in tumor cells. The research further confirmed in clinical samples that high expression of PITPα/β is closely associated with poor prognosis in gastric cancer patients, revealing PITPα/β as a potential new target for gastric cancer diagnosis and treatment.

This paper focuses on the marine natural peptide Microcolin H. To further explore its anti-tumor activity and mechanism, the total synthesis of the Microcolin H molecule was first achieved with a single batch yield exceeding 200mg, effectively addressing the material source issue for this type of natural product. Secondly, research at the cellular level revealed that Microcolin H exhibits nanomolar-level inhibitory activity against various tumor cells, including gastric cancer, lung cancer, pancreatic cancer, and liver cancer. Furthermore, using chemical proteomics technology, the direct target of Microcolin H was identified as phosphatidylinositol transfer protein α/β (PITPα/β). The confirmation of PITPα/β as the direct target for Microcolin H's anti-tumor activity was supported by protein thermal stability assays, molecular dynamics simulations, and the observation that knockout of PITPα/PITPβ in gastric cancer cells resulted in the loss of Microcolin H response.

Autophagy is a metabolic process of cellular self-degradation. By inducing autophagy, abnormal proteins and organelles within tumor cells can be cleared, blocking tumor survival and spread, thus providing new strategies and approaches for cancer treatment. This study found that Microcolin H significantly induces the conversion of LC3Ⅰ to LC3Ⅱ in tumor cells and increases the formation and accumulation of autophagosomes in GFP-RFP-Hela cells. Knocking out PITPα/PITPβ leads to the emergence of an autophagic phenotype and loss of response to Microcolin H treatment, confirming that Microcolin H induces autophagy-mediated death in tumor cells. Finally, Microcolin H also demonstrated strong anti-tumor activity in animal models, with a tumor inhibition rate of 74.2% in the 10mg/kg treatment group, without noticeable toxic side effects. Meanwhile, the autophagy inhibitor HCQ significantly weakened the anti-tumor effect of Microcolin H in vivo, further proving that Microcolin H exerts its anti-tumor activity by inducing autophagy.

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Professor Runhong Liu from East China University of Science and Technology published an article titled "Peptide-Mimicking Poly(2-oxazoline)s Possessing Potent Antifungal Activity and BBB Penetrating Property to Treat Invasive Infections and Meningitis" in JACS.

The article points out that invasive fungal infections are mainly caused by three types of fungi: Candida, Cryptococcus, and Aspergillus, resulting in nearly two million deaths annually. The primary reason for this global challenge is the very limited number of antifungal drugs available clinically, which often come with side effects such as hepatotoxicity and nephrotoxicity. Moreover, most antifungal drugs have poor blood-brain barrier (BBB) penetration, leading to low efficacy in treating meningitis.

The challenges in effectively treating invasive infections and meningitis currently lie in two main aspects: developing highly permeable antifungal drugs that are both highly effective and low in toxicity, and enhancing the ability to penetrate the blood-brain barrier (BBB). Modifying drug molecules with cell-penetrating peptides (CPPs), such as the TAT penetrating peptide (YGRKKRRQRRR) and polyarginine, is considered a promising strategy. However, this approach faces difficulties in achieving success due to the complexity of conjugation reactions, challenges in purifying conjugated products, and reduced antifungal activity after conjugation.

In the article, the author explores CPP mimicry strategies by introducing high-density guanidino groups and reports arginine-like antifungal polymers. In this paper, the author designs and synthesizes a guanidine-rich mimic of CPP polyarginine, poly(2-oxazoline), whose antifungal activity and BBB permeability can be modulated by adjusting the length of the side-chain spacer. Moreover, due to the excellent biocompatibility of poly(2-oxazoline), this CPP mimicry design strategy holds promising application prospects in treating drug-resistant fungal infections, including meningitis.

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Professor Samuel H. Gellman from the Department of Chemistry at the University of Wisconsin-Madison published an article titled "Thioamide Analogues of MHC I Antigen Peptides" in JACS.

The article points out that synthetic peptides binding to MHC I antigen epitopes can induce antigen-specific CD8 T cell responses, thus having the potential to be developed into vaccines. However, short peptides containing L-α-amino acid residues are highly susceptible to protease cleavage, which limits the development of peptide vaccines. Currently, there is no modification strategy for peptide antigens that can reduce protease cleavage while retaining MHC I recognition characteristics. Therefore, the authors attempted a modification strategy of replacing the peptide backbone amide with a thioamide.

In the article, the author selected the highly conserved immunodominant epitope GIL derived from the M1 protein of the influenza A virus, which can bind to human leukocyte antigen-A2 (HLA-A2), and constructed different monosubstituted thioantigens of this peptide. First, the author aimed to measure the ability of the thioantigens to stabilize HLA-A2 on the surface of T2 cells. To achieve this, the author used a fluorescently labeled anti-HLA-A2 antibody and quantitatively determined the levels of peptide+HLA-A2 (pHLA-A2) complexes on the cell surface via flow cytometry. The results showed that most of the monosubstituted thioantigens had an equal or higher binding affinity to HLA-A2 compared to the natural antigen. Next, the author assessed CD8 T-cell recognition of pHLA-A2 complexes presented by T2 cells and quantified the T-cell immune response by measuring IFN-γ secretion through ELISA. The results indicated that although all monosubstituted thioantigens could stimulate CD8 T cells to secrete IFN-γ, their efficacy was slightly weaker than that of the natural antigen. Subsequently, based on the T-cell activation results of the monosubstituted thioantigens, the author designed several multisubstituted thioantigens and found that they possessed HLA-A2 binding capabilities comparable to the natural antigen but demonstrated a significantly stronger ability to activate T cells.

Finally, the author used proteinase K to test the sensitivity of multi-substituted thioantigens to enzymatic cleavage. The results showed that the half-life of 1,5,8-substituted GIL significantly increased. In contrast, the half-life of 1,4,8-substituted GIL did not change明显, indicating that thioamide substitution at specific positions can protect the overall hydrolysis of the peptide. Additionally, the author selected the immunogenic epitope ELA derived from melanoma antigen A protein to construct the same mono-substituted and multi-substituted antigens, and tested their HLA-A2 binding ability, T-cell activation ability, and proteinase K hydrolysis half-life.

In general, the author of this article utilized a peptide modification strategy involving thioamide substitution for amide, which reduced the sensitivity of peptides to proteolytic hydrolysis while maintaining HLA-A2's ability to recognize antigenic peptides and the activation effect of the antigenic peptide + HLA-A2 complex on T cells.