(4eo) Peptide-Functionalized Materials for Bioprocessing, Molecular Identification, and Drug Delivery

Peptides are an attractive class of molecules for a variety of applications due to their high degree of chemical diversity and their biocompatibility. Additionally, this class of molecules is amenable to high-throughput combinatorial chemistry to create large libraries with controllable properties for identifying peptides with desired attributes. Leveraging my expertise in multimodal chromatography from my PhD and industrial experiences with my expertise in high-throughput peptide synthesis and combinatorial chemistry in my postdoc, my lab will develop advanced peptide-functionalized sorptive materials for a broad range of applications extending from biomanufacturing to proteomics to drug discovery and delivery.

Research & Professional Background:

PhD Student – RPI (2014-2019):

As a PhD student in Steve Cramer’s group at RPI I studied the interactions between multimodal chromatography resins and recombinant protein therapeutics. During this time, I created a range of mathematical frameworks for quantifying and characterizing orthogonality, or the degree to which complex multimodal resins interact differently with proteins. Using these frameworks, I developed high-throughput experimental and computational workflows to rapidly design integrated purification processes for difficult-to-purify proteins, resulting in several patents. Applying these tools, I developed purification processes for several therapeutics as part of a DARPA project aimed at creating a portable biologics-on-demand system for producing, purifying, and formulating medicines in the field.

Purification Scientist - Amgen (2019-2021):

Leveraging my expertise in chromatography and the process development tools that I developed during my PhD, I joined Amgen’s biologics division as a purification scientist. As the downstream lead on three pipeline molecules, I lead several teams in successfully developing purification processes while expanding my expertise to other sorption-based processes including membrane and filtration-based separation strategies. In addition to pipeline efforts, I was the downstream team lead in a cross-functional technology development effort resulting in the redesign of Amgen’s downstream platform along with several patent applications. I also served as an advisory board member for reviewing grant proposals from academic institutes as part of the MAST consortium focused on funding and collaborating with academic labs to advance upstream and downstream technologies. Additionally, as a joint steering committee member collaborating with several biotechnology supply companies, I provided recommendations for product development of new technologies needed in the biologics purification space. Through these experiences, I gained valuable insight into the inner workings of the downstream bioprocessing industry, allowing me to better understand what key technological advances will disrupt the field.

Postdoctoral Associate – MIT (2021-Present):

Inspired to address these bioprocessing needs, I chose to pursue a postdoc focused on peptide synthesis and design with the goal to ultimately create peptide-functionalized sorption materials in my independent career. As a postdoc working with Bradley Pentelute in the MIT Chemistry department, I am gaining expertise in drug discovery and high-throughput combinatorial chemistry techniques involving synthesis and screening of large libraries of peptide and peptide-mimetic drugs. My current research efforts focus on high-throughput discovery of serum-binding peptides for the half-life extension of small molecule drugs whose efficacy is hindered by rapid renal clearance. Additionally, I am working on the discovery of cell penetrating peptides designed to uniquely target specific cell types for enhanced drug delivery and efficacy.

Research Interests:

Advanced Separations Materials for Biomanufacturing

In bioprocessing, chromatography, membranes, and depth filters are among the most commonly used materials to purify life-saving therapies ranging from biologics to small molecule drugs and vaccines. By creating large synthetic libraries incorporating non-canonical amino acids, the Vecchiarello group will develop peptide and peptide-like functionalized materials for dramatically improving the capacity, selectivity, protease stability, and lifetime of these bioprocessing-relevant materials. Additionally, we will leverage novel methods developed during my PhD for quantifying the degree of orthogonal selectivities between ligands and proteins to develop new multimodal chromatography resins that behave synergistically and efficiently when operated together. The screening platform that we develop will pave the way for the next-generation of separation materials designed for newly emerging and difficult-to-purify therapeutics.

Peptide-Based Chromatographic Supports for High-Throughput Molecular Identification:

As an analytical tool, chromatography is used with mass spectrometry (LC-MS) to identify molecules in complex mixtures and has fueled many fields including proteomics, protein cross interaction studies, metabolomics, and drug discovery. The chromatography resins that currently exist rely on single-mode interactions and often fail to adequately separate molecules for identification by MS. Using combinatorial chemistry to generate billion-member libraries, my group will develop new peptide-based HPLC resins specifically designed to optimally separate important classes of molecules including metabolites, peptides, and small molecule drug candidates. Additionally, we will take advantage of recent developments in 2-dimension liquid chromatography (2D-LC) technology to design orthogonally selective sets of resins optimized for different applications. Ultimately, by leveraging these large library datasets in combination with machine learning, we will create models enabling in silico identification and generation of optimal “designer” HPLC peptide resins for separating and identifying molecules and compounds in any mixture.

Intelligent Drug Delivery Vehicles using Stimuli-Responsive Peptide-Decorated Nanoparticles

Mesoporous silica nanoparticles have recently gained significant attention as drug delivery systems due to their ability to carry high payloads of cancer-targeting medicines while exhibiting low immunogenicity and low renal clearance. These silica nanoparticles can be imbued with chemical moieties for a variety of purposes including cell-specific targeting, controlled drug release kinetics, and stimuli-responsive “gate-keeping” to release a toxic drug without off-target effects. Using combinatorial chemistry to generate large, high diversity libraries of peptides directly onto silica nanoparticles, the Vecchiarello group will develop a platform for the discovery of peptides functionalized onto the surface of nanoparticles specifically designed to bind cell receptor proteins unique to malignant cells. We will also design drug delivery systems with highly controllable payload release using pore-blocking “gatekeeper” peptides with conformational switches enabling drug release only in the unique environments within tumor cells. Additionally, to control release rate profiles from nanoparticles we will identify peptide-payload conjugates with desirable degradation kinetics for creating tunable release rate delivery systems.

Teaching Interests:

My experimental and modelling background in chromatography makes me particularly suited to teach courses related to Separations as well as Transport Phenomena. Having studied chemical engineering both in undergraduate and graduate school, however, I am also well-suited to teach any core chemical engineering course. Additionally, I would be interested in developing a graduate level course specifically focused on chromatographic separations.

As a professor, I will:

1.) Encourage collaborative environments through active learning and group homeworks and projects.

2.) Excite and prepare students for possible career trajectories using an invited panel of industrial guest speakers from my network.

3.) Facilitate student learning by providing daily classroom recaps, online access to classroom material, and additional help to ensure that students understand the material.