Kiss Krisztina, Ránky Soma, Gyulai Zsuzsanna, Molnár László
Tavanta Therapeutics Hungary Zrt., H-1138 Budapest, Hungary; Department of Organic Chemistry and Technology, Budapest University of Technology and Economics (BME), H-1111 Budapest, Hungary.
Tavanta Therapeutics Hungary Zrt., H-1138 Budapest, Hungary.
SLAS Technol. 2023 Apr;28(2):89-97. doi: 10.1016/j.slast.2023.01.002. Epub 2023 Jan 14.
The development of peptide-based pharmaceutics is a hot topic in the pharmaceutical industry and in basic research. However, from the research and development perspective there is an unmet need for new, alternative, solid-phase peptide synthesizers that are highly efficient, automated, robust, able to synthetize peptides in parallel, inexpensive (to obtain and operate), have potential to be scaled up, and even comply with the principles of green chemistry. Moreover, a peptide synthesizer of this type could also fill the gap in university research, and therefore speed the advancement of peptide-based pharmaceutical options. This paper presents a Tecan add-on peptide synthesizer (TaPSy), which has operational flexibility (coupling time: 15-30 min), can handle all manual synthesis methods, and is economical (solvent use: 34.5 mL/cycle, while handling 0.49 mmol scale/reactor, even with ≤3 equivalents of activated amino acid derivatives). Moreover, it can carry out parallel synthesis of up to 12 different peptides (0.49 mmol scale in each). TaPSy uses no heating or high pressure, while it is still resistant to external influences (operating conditions: atmospheric pressure, room temperature 20-40 ˚C, including high [>70%] relative humidity). The system's solvent can also be switched from DMF to a green and biorenewable solvent, γ-valerolactone (GVL), without further adjustment. The designed TaPSy system can produce peptides with high purity (>70%), even with the green GVL solvent alternative. In this paper we demonstrate the optimization path of a newly developed peptide synthesizer in the context of coupling reagents, reaction time and reagent equivalents applying for a synthesis of a model peptide. We compare the results by analytical characteristics (purity of raw material, crude yield, yield) and calculated overall cost of the syntheses of one mg of crude peptide using a specified set of reaction conditions.
基于肽的药物研发是制药行业和基础研究中的一个热门话题。然而，从研发角度来看，对于新型、替代的高效、自动化、稳健、能够并行合成肽、价格低廉（购置和运行成本）、具有扩大规模潜力甚至符合绿色化学原则的固相肽合成仪仍存在未满足的需求。此外，这种类型的肽合成仪还可以填补大学研究的空白，从而加速基于肽的药物选择的进展。本文介绍了一种帝肯附加肽合成仪（TaPSy），它具有操作灵活性（偶联时间：15 - 30分钟），可以处理所有手动合成方法，并且经济实惠（溶剂使用量：34.5毫升/循环，同时处理0.49毫摩尔规模/反应器，即使使用≤3当量的活化氨基酸衍生物）。此外，它可以并行合成多达12种不同的肽（每种0.49毫摩尔规模）。TaPSy无需加热或高压，同时仍能抵抗外部影响（操作条件：大气压，室温20 - 40˚C，包括高[>70%]相对湿度）。该系统的溶剂也可以从N,N - 二甲基甲酰胺（DMF）切换为绿色且可生物再生的溶剂γ - 戊内酯（GVL），无需进一步调整。所设计的TaPSy系统即使使用绿色GVL溶剂替代物也能生产高纯度（>70%）的肽。在本文中，我们展示了在应用于模型肽合成的偶联试剂、反应时间和试剂当量的背景下新开发的肽合成仪的优化路径。我们通过分析特性（原料纯度、粗产率、产率）以及使用指定反应条件计算合成一毫克粗肽的总成本来比较结果。
