Prof Raj Rajagopalan (Singapore)
Prof Bernhardt Trout (MIT)
The Flagship project, Molecular Engineering of Bio/Chemical Pathways & Process Science for the Pharmaceutical Industry, addresses an area of industrial practice that is important for the future of Singapore's industry, specifically the pharmaceutical industry. The Flagship project consist of 3 thrusts, metabolic engineering, chemical catalysis and downstream processing, which complement one another with the expectations of great results for the development of pharmaceuticals for Singapore. Specifically, the research program will focus on developing new technologies and cutting edge methods for the production, synthesis, separation, and formulation of pharmaceuticals, with a focus on chemical pharmaceuticals. The strategic roadmap and the connections between the flagship and inter-university projects are outlined in Figure 1, as detailed below.
The first thrust focuses on metabolic engineering, where molecular biotechnology is used to engineer pathways for the synthesis of chiral compounds and other Active Pharmaceutical Ingredients (APIs). The objectives for this program are to discover new clones and techniques for bioconversion; to develop tools to enable rapid, modularized approaches to recombinant biocatalyst construction; to engineer processes with enhanced bioconversion efficiencies for chiral compounds with high enantiometric excess; to enhance the efficiency of synthesis of valuable pharmaceuticals, such as Artemisinin (an anti-malaria drug), and to combine biocatalysis in vitro with co-factor regeneration, thus, solving important current technological problems.
A second focus area of the flagship project is chemical catalysis, where we target to efficiently synthesize chiral compounds by designing catalysts at the molecular-nanometer scale. The objectives for this project involve the synthesis of novel homogeneous organopalladium complexes for carbonylation reactions at low carbon monoxide pressures and moderate temperatures, which will have a major impact on the synthesis of esters and amides in the pharmaceuticals industry; the development of new chiral indium complexes that are water-stable and oxygen-tolerant for catalyzing various organic transformations, leading to not only environmentally friendly processes, but also simplified synthetic strategies; and the design and synthesis of nanoporous supports to immobilize chiral organometallic complexes, facilitating the recovery and reuse of the proposed organometallic ligands and leading to more efficient synthesis of chiral pharmaceuticals via continuous reactor schemes.
Downstream processing for the development of novel separation and purification concepts is the third pillar of the flagship project, whereby molecular engineering is used to achieve isolation, purification and formulation of proteins and small molecular drugs. In this part of the flagship project, we will develop new, commercially viable methods for separations, study interactions among biological molecules, and engineer novel formulations for biotherapeutics. This work has the potential to enhance significantly industrial efficiency via new processing methods and new analytical approaches. Another aim is the development of new means of delivery of biopharmaceuticals.
Seven Inter-University research projects have been assembled. The IUPs are compatible with the Flagship theme, while not having direct overlap.
Inter-University Project 1: Development of New Catalysts for Carbonylation Reactions of Importance to Pharmaceutical Manufacturing
Project members: Prof. Steve Buchwald (MIT), Prof. TP Loh (NTU), Prof. Jackie Y Ying (IBN).
The purpose of this project is to develop new catalysts that allow for the ready preparation of carboxylic acids, esters and amides. Chemical processes that can be utilized to carry out important chemical transformations in an environmentally benign, safe and efficient manner are extremely important in the pharmaceutical industry.
Inter-University Project 2: Novel Biocatalysis in Nanosystems
Project members: Prof. Jim Yang Lee (NUS), Prof. Daniel IC Wang (MIT)
Biocatalysis and metabolic engineering is one of the three thrusts in the Flagship Project with its main objectives in the use of biological systems for the synthesis of chiral chemicals. In this project we will make use of biological systems for the synthesis of biocatalytic nanosystems. It has been known that a number of algal (Chorella vulgaris) and microbial (Aspergillus niger) extracts are able to transform metal salts (e.g. gold) and convert the soluble metals to the reduced state (e.g. sold gold, Au0). These preparations will be combined with methods of nanoparticle preparation in order to create novel biocatalysts at the nanoparticle scale.
Inter-University Project 3: Microarray Monitoring in Chiral Synthesis and Biosynthesis
Project members: Zhiqiang Gao (BTI), Prof. Steve Buchwald (MIT), Prof. Miranda GS Yap (NUS and BTI), Prof. Gregory Stephanopoulos (MIT)
A major theme in the Flagship project is the microbial, biological or chemical synthesis of chiral chemicals. Within the scope of this theme, as well as the downstream processing of product recovery, methods for the rapid and sensitive monitoring on the chiral products would greatly enhance the overall project goals. In this Inter-University project we will examine a new concept for the monitoring of the chirality of the various products within the goals of the Flagship Research Projects. To this end, microarray technology be explored as the basis for the detection of the amount and product chirality in a high throughput manner.
Inter-University Project 4: Monitoring and Sensing: Microfluidic Systems
Project members: Prof. Miranda GS Yap (NUS and BTI), Prof. Pat Doyle (MIT) and Prof. Daniel IC Wang (MIT)
With the event of microarray and microfluidic technologies, there is a great opportunity to interface these technologies for the monitoring and sensing of biochemical and chemical reactions. In addition, the developments in generating monoclonal antibodies which have unique specificities and are able to detect analytes in extremely low concentrations offer an intriguing concept in the use of microarrays in combination with microfluidics in a multiplex mode and monitor a multitude of products simultaneously. The model system this Inter-University Project has selected is the monitoring of glycans which have been considered as small molecule drugs or as an aid in determining glycoprotein structures. In either case, the number of glycan that needs to be determined qualitatively and quantitatively will be quite large. Using microarray technology with microfluidics, it is our belief simultaneous monitoring of various glycans is possible. In this project we propose to develop a glycochip which will be able to perform in real-time and on-line monitoring of glycan structures and quantify glycan concentrations of glycoprotein in mammalian cell systems.
Inter-University Project 5: Dynamic Control of Separation Environment
Project members: Prof. Michael Tam (NTU), Prof. T. Alan Hatton (MIT), Prof. Ken A Smith (MIT)
Self-assembling surfactant and polymer micellar systems that respond to externally applied stimuli such as temperature, light, oxidation potential, etc., will be used to tailor the separation environment in capillary chromatographic and microfluidic reaction/separation devices. We will explore the use of spatially and temporally varying irradiation patterns, temperature distributions, and/or electrode potentials along the length of microfabricated microfluidic channels for the dynamic control of the distribution of solubilization capacities and interaction affinities in the devices. This strategy will be used to optimize staged or chromatographic-type separation operations for the high throughput measurement of important classes of intracellular molecules extracted from cells and tissues.
Inter-University Project 6: Tools for Pharmaceutical Polymorph Prediction
Project members: Ning Shan (ICES), Prof. Mark Saeys (NUS), Prof. Bernhardt L Trout (MIT)
The properties of pharmaceuticals are not only dictated by the chemical composition of the active molecules, but also by their crystal form. Different crystal forms are called polymorphs, and different crystal forms can have very different properties, such as rates of dissolution etc. In fact, part of the submission and approval of pharmaceuticals is based on the polymorph produced. Problems arise when (1) the polymorph changes during manufacturing, as what happened to Abbott pharmaceuticals with Ritaovir, and (2) when a competitor discovers a new polymorph and can develop a different drug composition based on it. The holy grail of pharmaceutical processing is to predict the phase diagram of new pharmaceuticals. This project will focus on developing new tools to accomplish this goal, using new theoretical methods developed by the three PI's.
Inter-University Project 7: Analytical and Preparative Enantioseparations of Chiral Pharmaceuticals
Project members: Prof. CB Ching (NTU), Prof. SC Ng (NTU) and Prof. A Rajendran (NTU)
This project entails the development of novel and efficacious chiral stationary phases (CSP) for analytical through to process enantioseparations via Supercritical Fluid Chromatography. Preparative SFC is a relatively new technology and only recently publications are appearing in the open literature. It is considered a “green” process as it substantially reduces the use of environmentally harmful organic solvents by replacing them with carbon dioxide (CO2) (the most commonly used supercritical fluid). Moreover, the properties of supercritical fluids CO2 enable faster and more efficient separations as compared to HPLC. This project capitalizes on the complementary expertise of the Prof. CB Ching in molecular design of chiral separations materials and the SFC process and optimization expertise of Rajandran.
Strategic Road Map for the Research program with CPE
Institute of Chemical and Engineering Sciences
Institute of Bioengineering and Nanotechnology
Bioprocessing Technology Institute