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From lead to market: chemical approaches to transform peptides into therapeutics 从先导到市场：将多肽转化为治疗药物的化学方法。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.01.009
Caitlin L. Gare , Andrew M. White , Lara R. Malins
Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the ‘drug-like’ properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.
多肽是一种强大的药物形态，具有接近困难靶标的潜力。这种认识是它们在全球制药市场增长的基础，在过去十年中，多肽占FDA批准的药物的8%。目前，肽治疗领域正在不断发展，高通量显示技术推动了肽导联的识别，增强了多样性。然而，化学修饰对于改善多肽的“类药物”特性并最终将其转化为市场仍然是必不可少的。在这篇综述中，我们探讨了两种最近的治疗候选药物（semaglutide，一种肽激素类似物，和MK-0616，一种mRNA显示衍生的候选药物）作为案例研究，强调了改善药代动力学（PK）和效价的一般方法。我们也强调在药物化学的进步和高效肽疗法的优化之间的关键联系。
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引用次数: 0
Decoding PETase diversity through global landscape profiling: toward superior enzymes for plastic recycling 通过全球景观分析解码PETase多样性：迈向塑料回收的优质酶。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.03.012
Yoonjoo Seo , Na Wei
A recent study by Seo, Hong, Park, et al. maps the global fitness landscape of PET-degrading enzymes, identifying superior PETases for plastic depolymerization. The engineered high-performance variant surpasses benchmarks under industrial conditions. This study provides a powerful framework for enzyme discovery, advancing biocatalytic solutions for plastic waste recycling.
Seo、Hong、Park 等人最近的一项研究绘制了 PET 降解酶的全球适应性图谱，确定了用于塑料解聚的优质 PET 酶。工程化的高性能变体超越了工业条件下的基准。这项研究为酶的发现提供了一个强大的框架，推动了塑料废物回收的生物催化解决方案。
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引用次数: 0
Subscription and Copyright Information 订阅及版权资料
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/S0968-0004(25)00116-1
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引用次数: 0
Joan J. Guinovart (1947–2025) Joan J. Guinovart （1947-2025）
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.03.006
Jordi Duran , Matthew S. Gentry
Joan J. Guinovart i Cirera, Emeritus Professor of Biochemistry and Molecular Biology, University of Barcelona (UB), and IRB Barcelona Emeritus Professor, passed away on January 1, 2025, at the age of 77 due to complications from pancreatic cancer. Dr Guinovart was a renowned biochemist celebrated for his pioneering research on glycogen metabolism and his influential leadership in science.
Joan J. Guinovart i Cirera，巴塞罗那大学（UB）生物化学和分子生物学名誉教授，巴塞罗那IRB名誉教授，因胰腺癌并发症于2025年1月1日去世，享年77岁。Guinovart博士是一位著名的生物化学家，因其在糖原代谢方面的开创性研究和他在科学领域的影响力而闻名。
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引用次数: 0
Decoding human chemical reprogramming: mechanisms and principles 解码人类化学重编程：机制和原理。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.03.004
Lin Cheng , Yanglu Wang , Jingyang Guan , Hongkui Deng
Pluripotent stem cells hold great promise as an unlimited resource for regenerative medicine due to their capacity to self-renew and differentiate into various cell types. Chemical reprogramming using small molecules precisely regulates cell signaling pathways and epigenetic states, providing a novel approach for generating human pluripotent stem cells. Since its successful establishment in 2022, human chemical reprogramming has rapidly achieved significant progress, demonstrating its significant potential in regenerative medicine. Mechanistic analyses have revealed distinct molecular pathways and regulatory mechanisms unique to chemical reprogramming, differing from traditional transcription-factor-driven methods. In this review we highlight recent advancements in our understanding of the mechanisms of human chemical reprogramming, with the goal of enhancing insights into the principles of cell fate control and advancing regenerative medicine.
多能干细胞具有自我更新和分化为各种细胞类型的能力，因此作为再生医学的无限资源具有很大的前景。利用小分子化学重编程技术精确调控细胞信号通路和表观遗传状态，为人类多能干细胞的生成提供了一种新的途径。自2022年成功建立以来，人体化学重编程迅速取得了重大进展，显示出其在再生医学中的巨大潜力。机制分析揭示了化学重编程独特的分子途径和调节机制，不同于传统的转录因子驱动方法。在这篇综述中，我们重点介绍了人类化学重编程机制的最新进展，目的是加强对细胞命运控制原理的认识，促进再生医学的发展。
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引用次数: 0
Histone variants: expanding the epigenetic potential of neurons one amino acid at a time 组蛋白变异：一次一个氨基酸扩展神经元的表观遗传潜能。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.03.015
Bradley J. Lukasak , Erica Korb
Replication-independent histone variants play an essential role in postmitotic neurons. Here, we review how the subtle sequence differences of histone variants compared to their canonical counterparts underly neuronal function. We focus on variants H3.3, H2A.Z, H2A.X, macroH2A, and H2BE; all of which contain divergent sequences that coordinate a diverse set of outcomes. In particular, we highlight their role in neuronal development, plasticity, and memory, with an emphasis on how single amino acid changes can mediate these complex functions. Lastly, we comment on an emerging field of study evaluating the link between histone variants and neurological disorders. Future studies of histone variants will be important to furthering our understanding of neuronal function.
复制无关的组蛋白变异在有丝分裂后神经元中起重要作用。在这里，我们回顾了组蛋白变体的细微序列差异与它们的规范对应物在神经元功能下的差异。我们专注于变体H3.3, H2A。Z, H2A。X， macroH2A和H2BE；所有这些都包含不同的序列来协调不同的结果。特别是，我们强调了它们在神经元发育，可塑性和记忆中的作用，重点是单个氨基酸的变化如何介导这些复杂的功能。最后，我们评论了一个新兴的研究领域，评估组蛋白变异和神经系统疾病之间的联系。未来对组蛋白变异的研究将对我们进一步了解神经元功能具有重要意义。
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引用次数: 0
Plant steroids on the move: mechanisms of brassinosteroid export 运动中的植物类固醇：油菜素内酯出口机制。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.03.003
Zi-Liang Hu , Hong Wei , Linfeng Sun , Eugenia Russinova
Brassinosteroids (BRs) are essential plant steroidal hormones that regulate growth and development. The recent discoveries of ATP-binding cassette subfamily B (ABCB) members, ABCB19 and ABCB1, as BR transporters highlight the significance of active export to the apoplast in maintaining BR homeostasis and enabling effective signaling. This review focuses on the latest progress in understanding ABCB-mediated BR transport, with particular attention to the structural and functional characterization of arabidopsis ABCB19 and ABCB1. These findings reveal both conserved and distinct features in substrate recognition and transport mechanisms, providing valuable insights into their roles in hormonal regulation. Additionally, the evolutionary conservation of ABC transporters in mediating steroid-based signaling across biological kingdoms underscores their fundamental biological significance.
油菜素内酯（BRs）是调节植物生长发育的重要甾体激素。最近发现的atp结合盒亚家族B （ABCB）成员ABCB19和ABCB1作为BR转运体，强调了向外质主动输出在维持BR稳态和实现有效信号传导中的重要性。本文综述了abcb介导的BR转运的最新进展，重点介绍了拟南芥ABCB19和ABCB1的结构和功能特征。这些发现揭示了底物识别和运输机制的保守和独特特征，为它们在激素调节中的作用提供了有价值的见解。此外，ABC转运体在生物王国中介导类固醇信号传导的进化保护强调了它们的基本生物学意义。
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引用次数: 0
Engineering RiPP pathways: strategies for generating complex bioactive peptides 工程RiPP途径：生成复杂生物活性肽的策略。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.04.001
Ayoola B. Smith , Renee C. Ejindu , Jonathan R. Chekan
Historically, natural products have been essential sources of therapeutic agents, many of which are currently used to manage various diseases. In recent years, ribosomally synthesized and post-translationally modified peptides (RiPPs) have garnered considerable interest in drug discovery and development due to their biosynthetic plasticity and their ability to generate diverse bioactive structural scaffolds. Unfortunately, many RiPPs have suboptimal bioavailability and proteolytic stability, significantly limiting their clinical potential. Moreover, the complexity of RiPP structures makes total synthesis extremely difficult. These drawbacks necessitate pathway engineering to create derivatives with potentially optimized physicochemical properties. Herein, we review recent efforts to surmount pathway engineering challenges and to rationally modify components of RiPP pathways for new functions to derive new bioactive analogs.
从历史上看，天然产品一直是治疗剂的重要来源，其中许多目前用于治疗各种疾病。近年来，核糖体合成和翻译后修饰肽（RiPPs）由于其生物合成可塑性和产生多种生物活性结构支架的能力，在药物发现和开发中引起了相当大的兴趣。不幸的是，许多ripp的生物利用度和蛋白水解稳定性都不理想，这极大地限制了它们的临床潜力。此外，RiPP结构的复杂性使得全合成极为困难。这些缺点需要途径工程来创造具有潜在优化的物理化学性质的衍生物。在此，我们回顾了最近的努力，以克服途径工程的挑战，并合理地修改RiPP途径的新功能成分，以获得新的生物活性类似物。
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引用次数: 0
Advisory Board and Contents 咨询委员会及内容
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/S0968-0004(25)00113-6
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引用次数: 0
Modifying the modifiers: ubiquitination of ADP-ribosylation in human cells 修饰剂的修饰：人类细胞中adp -核糖基化的泛素化。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-06-01 DOI: 10.1016/j.tibs.2025.03.010
Karla L.H. Feijs-Žaja , Jonas Siefert , Roko Žaja
Ubiquitination and ADP-ribosylation are protein post-translational modifications (PTMs) which influence diverse protein properties. In vitro work has indicated that ubiquitin can be ADP-ribosylated and vice versa, ADP-ribose ubiquitinated. An exciting new study by Bejan et al. now demonstrates that ubiquitination of ADP-ribosylated proteins, termed MARUbylation, occurs in human cells.
泛素化和adp核糖基化是影响蛋白质多种特性的蛋白质翻译后修饰（PTMs）。体外研究表明，泛素可以被adp核糖基化，反之亦然，adp核糖泛素化。Bejan等人的一项令人兴奋的新研究表明，adp核糖化蛋白的泛素化（称为marubyation）发生在人类细胞中。
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