SBIR Phase I: Solid Phase Slug Flow (SPSF) for Drug Discovery

这个小型企业创新研究(SBIR)第一阶段项目的更广泛的影响/商业潜力是迅速使目前无法用传统技术制造的具有治疗相关的新分子成为可能。多肽代表着治疗药物市场日益增长的子集：目前约有68种多肽疗法获得批准；约140种多肽疗法处于临床试验阶段，另有500种多肽疗法处于临床前阶段，这意味着到2025年，市场规模将达到210亿美元，增至440亿美元。虽然多肽疗法因肿瘤、心血管疾病和代谢性疾病等适应症而闻名，但最近对个性化多肽疗法的兴趣有所增长。目前，合成多肽需要数周时间，而且非常耗费资源，几毫克的产品成本高达数百至数千美元。这些高昂的成本和漫长的筹备时间严重限制了研究人员在给定时间段内可以测试的分子数量，这是多肽治疗创新的主要瓶颈。更快地获得这些潜在的治疗相关分子将加速发现新的疗法。这个小企业创新研究(SBIR)第一阶段项目克服了肽制造的主要瓶颈。快速自动计算、耦合、切割和层析执行(RAC4E)平台可生产高纯度定制多肽。然而，为了进一步扩展控制工艺条件和实现实时工艺优化的能力，我们建议开发固相段塞流(SPSF)耦合，使用先进的工程和机器学习解决方案在合成过程中产生分子纯度，从而实现实时优化多肽链。结合这些解决方案将允许更快和更长长度的多肽生产，并显著减少下游提纯的需要。一旦完全实施，带有SPSF耦合的RAC4E平台将产生多肽库，其速度和纯度将显著增加用作机器学习输入的生物筛选数据的密度。该平台稍后将被扩展到cGMP制造环境中，加快新肽疗法进入临床的速度。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to rapidly enable new therapeutically relevant molecules currently impractical to manufacture with conventional techniques. Peptides represent a growing subset of the therapeutics market: there are about 68 currently approved peptide treatments; ~140 peptide treatments in clinical trials and another 500 peptide treatments in the preclinical stage, representing a $21 B market growing to $44 B by 2025. While peptides therapeutics are known for indications such as oncology, cardiovascular disease, and metabolic disease, recent interest in personalized peptide therapeutics has grown. Currently, peptides take weeks to synthesize and are tremendously resource-intensive, costing hundreds to thousands of dollars for a few milligrams of product. These high costs and long lead times severely limit the number of molecules a researcher can test in a given period of time, representing the primary bottleneck in peptide therapeutic innovation. Faster access to these potentially therapeutic relevant molecules will accelerate discovery of new therapeutics.This Small Business Innovation Research (SBIR) Phase I project overcomes the major bottlenecks of peptide manufacturing. The Rapid Automated Computation, Coupling, Cleavage, and Chromatography Execution (RAC4E) Platform produces high purity custom peptides. However, to further extend the ability to control process conditions and achieve real-time process optimization, we propose developing solid-phase slug flow (SPSF) coupling, using advanced engineering and machine learning solutions to generate purity in molecules during synthesis, enabling optimization of the peptide chain in real-time. Combining these solutions will allow the production of peptides both faster and at longer lengths, as well as dramatically reducing the need for downstream purification. Once fully implemented, the RAC4E platform with SPSF coupling will produce peptide librariesat a speed and purity that will significantly increase the density of biological screening data serving as machine learning inputs. The platform will be later be scaled into a cGMP manufacturing environment, accelerating the rate of entry for novel peptide therapeutics into the clinic.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.