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简介 2026年1月22日，Gajendra P. S. Raghava团队在bioRxiv发文，首次揭示了多肽通透性在人工膜与细胞测定间的机制性差异，并开发了一套基于堆叠集成机器学习的肽通透性预测模型PCPpred，性能媲美或超越现有先进方法。  🧩研究背景 在药物研发领域，肽类分子，特别是经过化学修饰和环化的肽，因其高特异性、可定制的生物功能以及对“难成药”靶点的识别能力，已成为一类极具前景的治疗候选药物。然而，相较于传统小分子药物，这类肽（尤其是环肽）往往面临口服生物利用度的重大挑战，其核心瓶颈在于细胞膜通透性不足。膜通透性受多种复杂因素影响，如分子大小、极性表面积、氢键供受体数量以及分子构象等，使得准确预测变得异常困难。传统的实验测定方法（如PAMPA、Caco-2等）虽为金标准，但耗时耗力、成本高昂，难以用于大规模早期筛选。因此，开发快速、准确的计算预测工具，对于加速肽类药物的理性设计与优化至关重要。  🧪主要结果 1. 揭示不同通透性测定方法间的根本差异，强调模型需“因测而异” 首先对来自CycPeptMPDB数据库的四种主流通透性测定数据（PAMPA、Caco-2、RRCK、MDCK）进行了系统性分析。通过比较描述符与通透性值之间的相关性，发现基于细胞的测定方法（Caco-2、RRCK、MDCK）彼此间高度一致（相关系数r在0.96-0.98之间），而人工膜测定方法PAMPA与这三者则呈现微弱甚至负相关。例如，在Caco-2中与通透性正相关最强的描述符AtomTypeEState.252，在PAMPA中相关性几乎为零。对483个共有的肽分子在不同测定中通透性值的直接比较也显示出显著的测定依赖性变异。这一关键发现表明，PAMPA作为细胞通透性替代模型的预测能力有限，其机制与细胞系统存在本质不同。因此，研究确立了开发“测定特异性”预测模型的必要性，而非追求一个统一的通用模型。 2. 构建多层次分子特征体系，全面刻画肽的化学空间 为精准预测，研究从肽的单体序列和SMILES表示法中，系统提取并计算了四大类多层次分子特征：1）原子级特征：通过RDKit获取元素组成、键合类型、电荷分布等23维基础特征；2）单体组成特征：基于385种不同单体类型的组成向量，精细编码非天然氨基酸修饰信息；3）物理化学描述符：利用RDKit、Mordred和PaDEL等开源工具，计算了涵盖拓扑、几何、疏水性、电子分布等性质的数千个2D和3D分子描述符；4）分子指纹与语言模型嵌入：生成包括Morgan、MACCS、Klekota-Roth等在内的14种分子指纹，以捕获子结构模式；同时，对预训练的化学语言模型（如ChemBERTa、MolFormer-XL）进行微调，从其最终隐藏层提取768维的SMILES嵌入向量，以捕捉丰富的化学语义和句法信息。这套复合特征体系为模型提供了全面且互补的分子表征。 3. 开发堆叠集成模型架构，融合多特征优势实现最优预测 基于上述特征，研究创新性地构建了一个两阶段的堆叠集成回归架构。第一阶段，针对每一类特征（描述符、指纹、嵌入、原子特征），分别独立训练包含十种不同机器学习算法（如LGBM、随机森林、XGBoost、SVR等）的“基学习器”面板，并采用五折交叉验证生成其预测结果作为“元特征”。第二阶段，将来自所有特征类型的所有基学习器的预测结果拼接，形成统一的元特征矩阵，再输入到最终的“元学习器”（如LGBM、随机森林）中进行训练，从而得到最终的通透性预测值。这种架构巧妙地融合了不同特征表示和不同算法的优势，增强了模型的鲁棒性与泛化能力。 4. 模型性能卓越，在关键测定中超越现有先进方法 在最大的数据集PAMPA（6960个肽）上，堆叠集成模型取得了最佳测试集性能：均方误差（MSE）为0.200，决定系数（R²）为0.685，皮尔逊相关系数（PCC）为0.830。在Caco-2数据集（1259个肽）上，尽管堆叠模型表现优异（R²=0.783），但仅使用Mordred计算的2D描述符训练的单模型达到了更优性能（MSE=0.129，R²=0.793，PCC=0.892），这凸显了在特定测定中，精心挑选的物理化学描述符本身已具备极强的预测力。与现有先进模型（如CPMP）相比，本研究提出的方法在PAMPA和Caco-2测定上均表现出可比或更优的性能（见原文表11），验证了其有效性。 5. 阐明化学修饰对通透性的测定依赖性影响 通过组成与描述符分析，研究揭示了化学修饰影响通透性的复杂机制。在PAMPA体系中，N-甲基化（如meL, meA）和大的疏水修饰通常通过增加脂溶性和屏蔽氢键供体来增强被动扩散，从而提升通透性。然而，在Caco-2细胞模型中，相同的N-甲基化修饰却可能因影响溶解性或触发外排泵机制而降低通透性。相反，一些极性修饰（如Asp-哌啶、O-叔丁基丝氨酸）在Caco-2中显示出通透性增强。D-型氨基酸在两种体系中的作用也相反。这些发现强调了通透性优化策略不能一概而论，必须考虑目标递送环境（人工膜 vs. 复杂细胞系统）的具体要求，核心在于平衡适度的亲脂性与可控的极性。 6. 创建开源可访问工具，推动领域应用与可重复性 为促进研究成果的广泛应用，团队开发了名为“PCPpred”的开源平台。该平台包括一个用户友好的网页服务器和一个独立的GitHub代码库。其突出特点是支持使用课题组自行开发的、人类可读的MAP格式来设计修饰肽，服务器可自动将其转换为SMILES格式，并计算所有特征，最终为用户提供跨四种测定的通透性预测结果及可视化。这一工具极大降低了计算预测的门槛，使化学家和生物学家无需编程或商业软件即可将通透性预测整合到其肽设计工作流中，体现了对科学可重复性和资源平等获取的承诺。 🔬结论 本研究通过系统分析不同通透性测定间的差异，构建了一个整合多层次分子特征的堆叠集成机器学习框架，成功实现了对修饰环肽膜通透性的高精度、测定特异性预测。模型在大型数据集上表现优异，并提供了对化学修饰影响机制的深刻见解。更重要的是，研究配套开发了完全开源、易于使用的计算工具PCPpred，将先进的预测能力转化为实践资源。这项工作不仅推进了肽类药物药代动力学性质的计算建模水平，也为基于数据的理性肽设计提供了一个强大、可及的新平台，有望显著加速具有良好口服生物利用度肽类药物的发现    引用文献： (1) Shendre, A.; Gahlot, P. S.; Raghava, G. P. S. PCPpred: An Assay-Specific Stacked Ensemble Framework for Predicting Membrane Permeability of Modified Peptides. bioRxiv 2026. https://doi.org/10.64898/2026.01.19.700485.  如果对本文的研究内容仍有疑问，点击下方小卡片，让【AMPX】AI小助手为您答疑解惑。支持24小时实时在线交流，并提供个性化咨询。⬇️ 了解更多抗菌肽设计前沿信息，欢迎支持，订阅、转发、分享！！！ 合作/投稿邮箱：ampx@chemoinfolab.com 声 明 本平台“原创”标识仅限编译原创性，不主张原文版权。转载旨在学术交流，不代表平台立场或验证内容真实性，原文版权归属原作者，权利人可申请撤稿。若编译内容存在疏漏，请联络 ampx@chemoinfolab.com 修正。

iStock, bo feng Some 200 rare disease therapies are at risk of losing eligibility for a pediatric priority review voucher, a recent analysis by the Rare Disease Company Coalition shows. That could mean $4 billion in missed revenue for already cash-strapped biotechs. More than $4 billion in reinvestment dollars will be left on the table if the rare pediatric disease priority review voucher program is not reinstated this week after having lapsed in December 2024. That’s according to a recent impact report issued by the Rare Disease Company Coalition. “That foregone value is very significant, particularly for small and emerging biotechs that operate on very tight margins and for patients who already have such limited treatment options,” Stacey Frisk, executive director of the Rare Disease Company Coalition (RDCC), told BioSpace , adding that 95% of rare diseases currently have no targeted treatments. Under the priority review voucher (PRV) rare disease program, which began in 2012, a sponsor files for the FDA’s Rare Pediatric Drug Designation. Then, if that drug is approved, the FDA grants a PRV, which can expedite the drug review timeline from 12 months to around 6 months. The vouchers can be bought and sold. At a going rate of around $150 million when the program sunset at the end of 2024, PRVs have provided a critical fundraising tool for tiny rare disease biotechs—money that often goes back into the rare disease pipeline. Now, at least a chunk of that funding is in jeopardy. An RDCC analysis of the rare disease pipeline showed that 200 therapies are at risk of losing eligibility for a PRV if the program is not reauthorized. Assuming that 37 of these therapies are likely to be approved without a PRV attached, Frisk said, “what that translates into is an estimated $4 billion in lost reinvestment potential.” Key legislation—dubbed the Mikaela Naylon Give Kids a Chance Act of 2025—passed the House on Thursday as part of a $1.2 trillion spending bill aimed at keeping the U.S. government open. It comes before the Senate this week. “We saw a really clear signal from the administration that they want Congress to act quickly to reauthorize the PRV program,” Frisk said, pointing to an email from Gary Andres, assistant secretary for legislation at the Department of Health and Human Services (HHS), to Senate Majority Leader John Thune advocating for the program. “HHS strongly supports reauthorization of the [rare pediatric disease] PRV program through September 30, 2029 as proposed in Section 5,” Andres wrote in the letter, which was viewed by BioSpace . Biotech has already been going through a tough time, underscored by funding challenges and the rapid emergence of Chinese innovation, Bo Cumbo, CEO of Solid Biosciences, a genetic medicines company focusing on rare neuromuscular diseases, told BioSpace . “The last five years for small startup companies, especially in the rare disease space, have been extremely challenging,” he said, “and the removal or the end of the priority review voucher will be just sort of that final straw that breaks the back of the rare disease companies.” By the Numbers First introduced in 2012 to encourage development of drugs for rare pediatric diseases affecting less than 200,000 people in the U.S., the PRV program has been highly successful. In 2024, the FDA handed out more rare pediatric PRVs than in any year since the scheme’s inception—in all, there have been 80, according to a BioSpace analysis . The highest price paid for a PRV was AbbVie’s $350 million purchase of United Therapeutics’ voucher in 2015. Earlier this month, Jazz Pharmaceuticals revealed the sale of a PRV attached to the August 2025 approval of glioma drug Modeyso for $200 million to an unnamed buyer. Rare diseases Priority Review Vouchers: By the Numbers A BioSpace analysis of all 80 priority review vouchers that have been handed out across the three FDA programs that offer them found that 2024 was the busiest year yet. Companies have disclosed spending $513 million on vouchers that were earned in 2024 so far. March 5, 2025 · 1 min read · Annalee Armstrong The PRV program began to wind down in December 2024, however, after Congress failed to pass legislation that would have renewed it. Under a temporary extension , rare disease drugs approved by Sept. 30, 2026, still qualify for a PRV, but without a renewal before then, no new vouchers will be granted. RDCC’s report showed that since the PRV program’s lapse, investors have grown more cautious. “Rare pediatric disease–focused companies are really having a more onerous time getting the capital they need to continue innovating in these disease areas that have really high unmet need,” Frisk said. A survey conducted by the organization revealed that for 85% of biotech executives, the PRV was a significant factor in their decision to pursue the development of rare pediatric disease assets; 35% have canceled or delayed programs in their pipeline since the program lapsed; and 50% expect further difficulties in accessing capital now that it has. “Right now, there’s a lack of predictability,” Justin To, CEO of skeletal dysplasia programs at BridgeBio, told BioSpace . “Without knowing whether or not Congress is going to reauthorize the program, that lack of predictability and that uncertainty really starts to kind of choke off investment in developing pediatric programs.” If Congress fails to reauthorize the program this week, the situation will only deteriorate, as biotech executives will have to make some tough calls—Cumbo among them. “If this rare disease voucher program is removed, you’re going to watch many of the smaller programs—[with] 10,000 or less patients—be cut, and they’ll be cut by someone like myself who is only thinking about how to survive as a company,” he said. “If you think about it, there are the haves and have-nots of disease states,” he continued. “There are markets that have shown to be very large where people could still put money to and they know that the risk versus reward can still be there.” By this calculation, Solid’s lead program, SGT-003 for Duchenne muscular dystrophy (DMD), which affects around 10,000 people in the U.S., would survive, Cumbo said. But for other rare diseases that are equally as fatal, “there has to be a lot of resources to sort of build the market. Those will be the disease states that are impacted.” Molybdenum cofactor deficiency (MoCD) Type A fits this description. In February 2021, BridgeBio won FDA approval for Nulibry, the first therapy to reduce the risk of mortality in patients with this ultra-rare disease. BridgeBio’s To credits the PRV program with being instrumental in bringing Nulibry to the market. “The reason why we were able to get that therapy approved was because of the pediatric review voucher,” he told BioSpace . While To noted that one of the company’s principles is to always put patients first, even if the economics don’t meet industry norms, “the PRV certainly makes it possible for us to develop medicines for ultra-rare diseases like we did for MoCD.” Ultimately, he said, “the PRV directly impacts how many of our rare-disease shots on goal we can fund and move into the clinic.” The program is also critical for earlier-stage companies like SynaptixBio, which launched in 2021 to tackle TUBB4a-related leukodystrophy, one of the world’s rarest diseases. “It’s difficult enough to get investment into early-stage companies,” SynaptixBio CEO Dan Williams told BioSpace , “but with rare diseases, where the market is much smaller, you really need to try everything you can to bring funding in.” The expedited regulatory pathway granted by a PRV or funds derived from its sale “derisk” rare disease drug development significantly, Williams said, allowing investors to come in at an early stage. Maintaining Momentum If the PRV program is reinstated this week, it would be a boon to a rare disease space that has seen significant regulatory momentum in recent months, making good on one of FDA Commissioner Marty Makary ’s first stated goals after taking office last year. In November 2025, the FDA introduced the plausible mechanism approval pathway for rare diseases, intended to expedite treatments “for products where a randomized trial is not feasible.” This followed the Rare Disease Evidence Principles framework in September that year to streamline the approval of therapies for ultrarare diseases, typically those affecting less than 1,000 people in the U.S. Rare diseases Rare Disease Experts See Futility in FDA’s Proposed Framework The FDA’s proposed Rare Disease Evidence Principles review process is a starting point for getting rare disease therapies across the finish line, but industry leaders say there are more concrete steps the regulator could take to help patients. September 22, 2025 · 5 min read · Dan Samorodnitsky Revenue estimates match the momentum. A recent report by ResearchAndMarkets.com has the orphan global drugs market reaching $611 billion by 2032—up from $247 billion last year. This reflects “ongoing regulatory evolution, targeted market incentives and increasing levels of investment,” according to the report’s authors. But failure to reauthorize the program will hobble this progress, experts who spoke with BioSpace agree. “Long term, if it doesn’t go through, I think we’ll see less financial institutes actually investing in rare diseases, and I think we’ll see less biotechs developing for rare diseases,” Williams said. “I think it’s going to really hit the rare disease industry quite hard.” .responsive-container { display: flex; flex-wrap: wrap; border: 1px solid #ededed; font-family: Helvetica, Arial, Sans-Serif; padding: 20px 20px 10px 20px; } .column-left { flex: 1; max-width: 45%; padding: 20px 20px 10px 20px; } .column-right { flex: 2; padding: 20px 20px 10px 20px; } @media (max-width: 768px) { .column-left, .column-right { max-width: 100%; flex: 100%; padding: 10px 0; } } Subscribe to ClinicaSpace! 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