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Carvalho, H, Branco R, Leite F, Matzapetakis M, Roque ACA, Iranzo O.  2019.  Hydrolytic zinc metallopeptides using a computational multi-state design approach. Catalysis Science Technology. 9(23):6723-6736. AbstractWebsite

Hydrolytic zinc enzymes are common targets for protein design. The versatility of the zinc chemistry can be combined with the usage of small protein scaffolds for biocatalytic applications. Despite this, the computational design of metal-containing proteins remains challenging due to the need to properly model protein–metal interactions. We addressed these issues by developing a computational multi-state design approach of artificial zinc hydrolases based on small protein scaffolds. The zinc-finger peptide Sp1f2 was redesigned to accommodate a catalytic zinc centre and the villin headpiece C-terminal subdomain HP35 was de novo designed for metal-binding and catalytic activity. Both metallopeptides exhibited metal-induced folding (KZnP,app ≈ 2 × 105 M−1) and hydrolytic activity (k2 ≈ 0.1 M−1 s−1) towards an ester substrate. By focusing on the inherent flexibility of small proteins and their interactions with the metal ion by molecular dynamics simulations and spectroscopic studies, we identified current limitations on computational design of metalloenzymes and propose how these can be overcome by integrating information of protein–metal interactions in long time scale simulations.

Barroso, T, Casimiro T, Ferraria A, Mattioli F, Aguiar-Ricardo A, Roque ACA.  2014.  Hybrid monoliths for magnetically-driven protein separations. Adv. Funct. Mater.. 24(28):4528–4541. AbstractWebsite

Monoliths represent powerful platforms for isolation of large molecules with high added value. This work presents a hybrid approach for antibody (Ab) capture and release. Using mostly natural polymers and clean processes, it is possible to create macroporous monoliths with well-defined porous networks, tuneable mechanical properties, and easy functionalization with a biomimetic ligand specific for Ab. Magnetic nanoparticles (MNPs) are embedded on the monolith network to confer a controlled magnetic response that facilitates and accelerates Ab recovery in the elution step. The hybrid monolithic systems prepared with agarose or chitosan/poly(vinyl alcohol) (PVA) blends exhibit promising binding capacities of Abs directly from cell-culture extracts (120 ± 10 mg Ab g−1 support) and controlled Ab magnetically-assisted elution yielding 95 ± 2% recovery. Moreover, a selective capture of mAbs directly from cell culture extracts is achieved yielding a final mAb preparation with 96% of purity.

Palma, SICJ, Roque ACA.  2017.  Hybrid Magnetic-Polymeric Iron Oxide Nanoprobes for Magnetic Resonance Imaging. Journal of Nanoscience and Nanotechnology. Volume 17(Number 7):4410-4431(22). AbstractWebsite

In the last decades, the advent of nanotechnology has driven the study and application of nanoscale versions of magnetic materials. Among the various nanoparticles under research, iron oxide magnetic nanoparticles (MNP), namely iron oxides magnetite (Fe3O4) and maghemite (γ-Fe2O3), have attracted particular interest due to their superparamagnetism, biocompatibility and biodegradability. MNP are thus ideal platforms to work on a cellular and molecular level in several biomedical applications. In particular, the use of MNP as contrast agents for biomedical imaging through Magnetic Resonance Imaging (MRI) has been explored extensively in the last 30 years, taking advantage of the versatility of MNP functionalization due to the available large surface-to-volume ratio. Polymers, either synthetic or natural, are the most common class of materials employed as coatings for MNP, allowing to customize nanoprobes properties such as size, shape, magnetic relaxation, as well as cell-nanoprobe interactions (for example, specificity towards tissue types, responsiveness to cellular environment features), therapeutic effects or combination with other imaging modalities. While most biopolymers have intrinsic biocompatibility and biodegradability properties and are greener products, synthetic polymers offer engineering versatility and possibility of being tailor-made with specific properties. This review covers the properties of nanoscale iron oxides, production and stabilization methods of such nanoparticles, and their biomedical applications, mainly focusing on the engineering of polymeric-MNP assemblies towards the development of new hybrid magnetic-polymeric MRI nanoprobes.

Pina, AS, Hussain A, Roque ACA.  2009.  An historical overview of drug discovery. Ligand-Macromolecule Interactions in Drug Discovery. (Roque, A. C. A., Ed.).:3-12., USA: Humana Press Inc. Abstract

Drug Discovery in modern times straddles three main periods. The first notable period can be traced to the nineteenth century where the basis of drug discovery relied on the serendipity of the medicinal chemists. The second period commenced around the early twentieth century when new drug structures were found, which contributed for a new era of antibiotics discovery. Based on these known structures, and with the development of powerful new techniques such as molecular modelling, combinatorial chemistry, and automated high-throughput screening, rapid advances occurred in drug discovery towards the end of the century. The period also was revolutionized by the emergence of recombinant DNA technology, where it became possible to develop potential drugs target candidates. With all the expansion of new technologies and the onset of the "Omics" revolution in the twenty-first century, the third period has kick-started with an increase in biopharmaceutical drugs approved by FDA/EMEA for therapeutic use.