The Baylor Synthesis and Drug-Lead discovery laboratory and MiniPharma teams are leading the optimization and scale-up synthesis of des-methyl pateamine A (DMPatA) in addition to the design and synthesis of novel pateamine A (PatA) derivatives with better mRNA selectivity. The presence of bound mRNA introduces another level of complexity yet offers an avenue for pateamine A derivatives to more efficiently distinguish between cancerous and normal cells. Cancerous cells, which require excessive levels of metabolic protein production to fuel abnormal growth, may be encoded by mRNA that differ in base composition to normal cells¹. A pateamine A derivative that binds tightly to mRNA found in cancerous cells but not to normal cells would selectively inhibit translation in cancerous cells.
To first design these selective derivatives, MiniPharma researchers perform in silico docking studies (molecular operating environment, MOE) using a recently determined X-ray crystal structure of DMPatA bound to its biological target (eIF4A) and mRNA (protein data bank code: 6XK1)³. The solved crystal structure includes a bound (AG)₅ polypyrimidine sequence; however, usage of the MOE RNA/DNA builder yields a unminimized crystal structure with a bound (UC)₅ polypurine sequence. Using structure-based design, interactions between DMPatA, eIF4A, and mRNA are analyzed and possible derivatives are modified. Resultant derivatives are docked into both polypyrimidine and polypurine complexes, with the difference in docking energies serving as a proxy for mRNA selectivity. Ease of synthesis and physical properties, such as lipophilicity, are also considered. New lead compounds are being designed and synthesized with the potential for better selectivity and improved physical properties required for a drug candidate.
- R. Chen, M. Zhu, R. R. Chaudhari, O. Robles, Y. Chen, W. Skillern, Q. Qin, W. Wierda, S. Zhang, K. G. Hull, D. Romo, W. Plunkett “Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia” Leukemia 2019, 33, 1663–1674.
- G. Schneider, J.T. Siveke, F. Eckel, R.M. Schmid “Pancreatic cancer: basic and clinical aspects” Gastroenterology 2005, 128,1606-1625.
- S. Naineni, J. Liang, K. Hull, R. Cencic, M. Zhu, P. Northcote, P. Teesdale-Spittle, B. Nagar, D. Romo, J. Pelletier “Functional mimicry revealed by the crystal structure of an eIF4A:RNA complex bound to the interfacial inhibitor, des-methyl Pateamine A” Cell Chem. Biol. 2021, 28, 1-10.