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Gonzalo Jiménez-Osés

Gonzalo Jiménez-Osés
Center for Cooperative Research in Biosciences | CIC bioGUNE · Compuational Chemistry Lab

Ph.D. in Chemistry

About

167
Publications
13,485
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Citations
Introduction
Computational design and screeening of functional enzymes for non-natural reactions. QM characterization of stereoselective mechanisms. Ab initio Molecular Dynamics for the study of non-classical reactions. Microsecond Molecular Dynamics for the study of proteins and materials. DFT analysis and characterization of non-covalent interactions.
Additional affiliations
October 2010 - April 2015
University of California, Los Angeles
Position
  • PostDoc Position
July 2007 - October 2010
University of Zaragoza
Position
  • Lecturer
October 2001 - July 2007
Universidad de La Rioja (Spain)
Position
  • PhD Student

Publications

Publications (167)
Article
Efficient methodologies for synthesizing enantiopure α-deuterated derivatives of serine, cysteine, selenocysteine, and 2,3-diaminopropanoic acid have been developed. H/D exchange was achieved by deprotonation of a chiral bicyclic serine equivalent followed by selective deuteration. Additionally, diastereoselective additions of thiols, selenols, and...
Article
Simvastatin is a top-selling cholesterol-lowering drug traditionally obtained through a semi-synthetic process starting from lovastatin. However, this process is cost-demanding and makes use of chemical reagents that can generate considerable waste. The sustainability concerns underlying the current semi-synthetic process encouraged us to immobiliz...
Article
Full-text available
Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylat...
Article
Full-text available
Chiral bicyclic N,O-acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N,O-acetalization/intramolecular transcarbamoylation reaction between conveniently protected l-isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereo...
Article
Full-text available
Protein conjugates are valuable tools for studying biological processes or producing therapeutics, such as antibody-drug conjugates. Despite the development of several protein conjugation strategies in recent years, the ability to modify one specific amino acid residue on a protein in the presence of other reactive side chains remains a challenge....
Article
Full-text available
Two years after its emergence, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several vaccines. The extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin conv...
Article
Full-text available
Antibody-drug conjugates (ADCs) are a class of targeted therapeutics used to selectively kill cancer cells. It is important that they remain intact in the bloodstream and release their payload in the target cancer cell for maximum efficacy and minimum toxicity. The development of effective ADCs requires the study of factors that can alter the stabi...
Article
Two phenylene based geometrical/isomeric triplet ortho- and para–dyads (o–3 and p–3, respectively) were synthesized and fully characterized using advanced photophysical tools and computations. In dyad o–3, the through-space donor-acceptor interactions led to simultaneous triplet energy transfer and charge transfer with identical kinetics. On the ot...
Article
Engineering of donor–acceptor light-harvesting systems based on geometrical features: applications in energy transfer & energy/photon upconversion.
Article
Pharmaceutical industry is progressively replacing the chemical synthesis of cholesterol‐lowering agents by enzymatic processes. The directed evolution of acyltransferase LovD was a breakthrough in the synthesis of simvastatin, although little is known about how the in vitro evolution path raised up an engineered variant (LovD9) with excellent bioc...
Article
Viruses are very attractive biomaterials owing to their capability as nanocarriers of genetic material. Efforts have been made to functionalize self-assembling viral protein capsids on their exterior or interior to selectively take up different payloads. PRD1 is a double-stranded DNA bacteriophage comprising an icosahedral protein outer capsid and...
Article
A multidisciplinary study to shed light on how pyrylium framewoks, as π-hole donors, establish π-π interactions is presented. The combination of CSD analysis, computational modelling (ab intitio, DFT and MD...
Article
Accurately determining the acid dissociation constants (Ka or their logarithmic form, pKa) of small molecules and large biomolecules has proven to be pivotal for the study different biological processes and developing new drugs. This Viewpoint summarizes some of the most common methodologies and recent advances described for pKa prediction using co...
Article
Hydrazone bond formation is a versatile reaction employed in several research fields. It is one of the most popular reversible reactions in dynamic combinatorial chemistry. Under physiological conditions, hydrazone exchange benefits from the addition of a nucleophilic catalyst. We report a mechanistic study and superior performance of electron-rich...
Article
This article presents an overview of recent computational studies dedicated to the analysis of binding between galectins and small-molecule ligands. We first present a summary of the most popular simulation techniques adopted for calculating binding poses and binding energies, and then discuss relevant examples reported in the literature for the th...
Article
The interaction of human galectin-8 and its two separate N-terminal and C-terminal carbohydrate recognition domains (CRD) to their natural ligands has been analysed using a synergistic combination of experimental NMR and ITC methods, and molecular dynamics simulations. Both domains bind the minimal epitopes N-acetyllactosamine (1) and Galβ1-3GalNAc...
Article
Full-text available
Cysteine plays a major role in the redox homeostasis and antioxidative defense mechanisms of many parasites of the phylum Apicomplexa. Of relevance to human health is Toxoplasma gondii, the causative agent of toxoplasmosis. A major route of cysteine biosynthesis in this parasite is the reverse transsulfuration pathway involving two key enzymes cyst...
Article
A cytochrome c heme protein was recently engineered to catalyze the formation of carbon-silicon bonds via carbene insertion into Si-H bonds, a reaction that was not previously known to be catalyzed by a protein. High chemoselectivity toward C-Si bond formation over competing C-N bond formation was achieved, although this trait was not screened for...
Article
Full-text available
The tandem-repeat Galectin-4 (Gal-4) contains two different domains covalently linked through a short flexible peptide. Both domains have been shown to bind preferentially to A and B histo blood group antigens with different affinities, although the binding details are not yet available. The biological relevance of these associations is unknown, al...
Article
Full-text available
This mini-review provides an overview of the enthalpy–entropy compensation phenomenon in the simulation of biomacromolecular recognition, with particular emphasis on ligand binding. We approach this complex phenomenon from the point of view of practical computational chemistry. Without providing a detailed description of the plethora of existing me...
Article
Full-text available
Protein oligomerization processes are widespread and of crucial importance to understand degenerative diseases and healthy regulatory pathways. One particular case is the homo-oligomerization of folded domains involving domain swapping, often found as a part of the protein homeostasis in the crowded cytosol, composed by a complex mixture of cosolut...
Preprint
Full-text available
Cystathionine beta-synthase (CBS), the pivotal enzyme of the reverse transsulfuration pathway, catalyzes the pyridoxal-5-phosphate-dependent condensation of serine with homocysteine to form cystathionine. Additionally, CBS performs alternative reactions that use homocysteine and cysteine as substrates leading to the endogenous biosynthesis of hydro...
Chapter
In this article, the chemistry of 1,2,3-dithiazoles and 1,2,3-oxathiazoles is covered from 2009 to 2018 inclusive. The 1,2,3-dithiazoles studied are: 1,2,3-dithiazolium cations, 1,2,3-dithiazolyl radicals, 1,2,3-dithiazole-5-ones and related thiones, imines and ylidene compounds, their 5,5-disubstituted derivatives, and their 2-oxides. 1,2,3-Oxathi...
Article
The first totally chemo- and diastereoselective 1,4-conjugate additions of Se-nucleophiles to a chiral bicyclic dehydroalanine (Dha) are described. The methodology is simple and does not require any catalyst, providing exceptional yields at room temperature, and involves the treatment of the corresponding diselenide compound with NaBH4 in the prese...
Article
Full-text available
Adjuvants are key immunostimulatory components in vaccine formulations that improve the immune response to the co‐administered antigen. The saponin natural product QS‐21 is one of the most promising immunoadjuvants in the development of vaccines against cancer and infectious diseases but suffers from limitations that have hampered its widespread hu...
Article
Methods that allow for chemical site-selective dual protein modification are scarce. Here, we provide proof-of-concept for the orthogonality and compatibility of a method for regioselective lysine modification with strategies for protein modification at cysteine and genetically encoded ketone-tagged amino acids. This sequential, orthogonal approach...
Article
Full-text available
Glycans possess unparalleled structural complexity arising from chemically similar monosaccharide building blocks, configurations of anomeric linkages and different branching patterns, potentially giving rise to many isomers. This level of complexity is one of the main reasons that identification of exact glycan structures in biological samples sti...
Article
Full-text available
Unprecedent structural details of the glycans of the RBD of SARS‐CoV‐2 spike glycoprotein have been revealed by NMR spectroscopy. Unexpected and non‐previously reported glycoepitopes have been detected. The interaction of the RBD glycoprotein with diverse human lectins has been scrutinized by exploiting the NMR signature of the ¹³C‐glycans. Our ana...
Article
Full-text available
The glycan structures of the receptor binding domain of the SARS-CoV2 spike glycoprotein expressed in human HEK293F cells have been studied by using NMR. The different possible interacting epitopes have been deeply analysed and characterized, providing evidence of the presence of glycan structures not found in previous MS-based analyses. The intera...
Preprint
div> Protein conjugates are valuable tools to create therapeutics, such as antibody-drug conjugates, or to study biological processes. Despite a number of protein conjugation strategies having been developed over recent years, the ability to modify one specific amino acid on a protein in the presence of other side chains with similar reactivity re...
Article
Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction of glycosidic scaffolds and glycoconjugates of biological and chemical interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the α- and β-glycosyl triflates, or...
Article
Hybrid peptides whose N-terminal residues are activated in the form of α-methylisoserine-derived cyclic sulfamidates exhibit a rich reactivity as electrophiles, allowing site- and stereoselective modifications at different backbone and sidechain positions. The unique properties of this scaffold allow the stereocontrolled late-stage functionalizatio...
Article
Full-text available
The chemistry of diazocompounds has generated a huge breadth of applications in the field of organic synthesis. Their versatility combined with their tuneable reactivity, stability and chemoselectivity makes diazo compounds desirable reagents for chemical biologists. Here, we describe a method for the precise installation of diazo-handles on protei...
Article
The highly diastereoselective 1,4-conjugate additions of several nitrogen nucleophiles to chiral bicyclic dehydroalanines have been assessed effectively at room temperature in good to excellent yields without needing any catalyst or additional base. This methodology is general, simple, oxygen and moisture tolerant, high-yielding, totally chemo- and...
Article
We have developed an azanorbornadiene bromovinyl sulfone reagent that allows cysteine‐selective bioconjugation. Subsequent reaction with dipyridyl tetrazine led to bond‐cleavage and formation of a pyrrole‐linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene‐tagged protein through inverse electron demand Diels–Alde...
Article
We have developed an azanorbornadiene bromovinyl sulfone reagent that allows cysteine‐selective bioconjugation. Subsequent reaction with dipyridyl tetrazine led to bond‐cleavage and formation of a pyrrole‐linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene‐tagged protein through inverse electron demand Diels–Alde...
Article
A green and efficient method for preparing lanthionine peptides by a highly chemoselective and stereochemically controlled procedure is presented. It involves an S-alkylation reaction, promoted by activated molecular sieves, on chiral cyclic sulfamidates, both N-protected and unprotected. Of note, the reaction yield was high also for cyclic sulfami...
Article
Carbohydrate/aromatic stacking represents a recurring key motif for the molecular recognition of glycosides, either by protein binding domains, enzymes or synthetic receptors. Interestingly, it has been proposed that aromatic residues might also assist in the formation/cleavage of glycosidic bonds by stabilizing positively charged oxocarbenium-like...
Chapter
This protocol details a novel bioconjugation strategy that uses a methanesulfonyl acrylate reagent that is directed to the most reactive lysine on human serum albumin, which enables the construction of chemically defined and stable bioconjugates. The reaction proceeds rapidly and a regioselective modification is achieved using a single molar equiva...
Article
Protein behavior is closely regulated by a plethora of post-translational modifications (PTMs). It is therefore desirable to develop approaches to design rational PTMs to modulate specific protein functions. Here, we report one such method, and we illustrate its successful implementation by potentiating the anti-aggregation activity of a molecular...
Article
A hungry bear is trying to catch some slippery fish from a river; this resembles the feeling of bioorganic chemists attempting the synthesis of very reactive, elusive compounds such as the cyclic dehydroalanine derivatives (4‐methylenoxazol‐5(4H)‐ones). Non‐destructive detection techniques such as NMR spectroscopy (the fishing net) allowed us (the...
Preprint
p>Strained alkenes and alkynes are the predominant dienophiles used in inverse electron-demand Diels-Alder (IEDDA) reactions, however, their instability, cross-reactivity and accessibility are problematic. Unstrained dienophiles, although physiologically stable and synthetically accessible, react with tetrazines significantly slower relative to str...
Article
Full-text available
We have developed [2.2.1]azabicyclic vinyl sulfone reagents that simultaneously enable cysteine-selective protein modification and introduce a handle for further bioorthogonal ligation. The reaction is fast and selective for cysteine relative to other amino acids that have nucleophilic side-chains, and the formed products are stable in human plasma...
Article
Quaternised vinyl‐ and alkynyl‐pyridine reagents were shown to react in an ultrafast and selective manner with several cysteine‐tagged proteins at near‐stoichiometric quantities. We have demonstrated that this method is able to create effectively a homogenous antibody‐drug conjugate that features a precise drug‐to‐antibody ratio of 2 that was stabl...
Article
Full-text available
Quaternised vinyl‐ and alkynyl‐pyridine reagents were shown to react in an ultrafast and selective manner with several cysteine‐tagged proteins at near‐stoichiometric quantities. We have demonstrated that this method is able to create effectively a homogenous antibody‐drug conjugate that features a precise drug‐to‐antibody ratio of 2 that was stabl...
Article
In addition to its usage for the study of biomolecules in living systems, bioorthogonal chemistry has emerged as a promising strategy to enable protein or drug activation in a spatially and temporally controlled manner. This study demonstrates the application of the bioorthogonal inverse electron‐demand Diels‐Alder (IEDDA) reaction to cleave trans‐...
Article
GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α-O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy to design potent antigen mimics based on modula...
Article
For the first time, a simple methodology for the chemical synthesis and utilization of highly reactive 4‐methylen‐oxazol‐5(4H)‐ones from serine is presented. These dehydroalanine derivatives, which resemble the natural 4‐methylideneimidazole‐5‐one (MIO) cofactor present in lyases and aminomutases, undergo rapid reaction with carbon nucleophiles suc...
Article
Full-text available
The secretion of peptides and proteins is essential for survival and ecological adaptation of bacteria. Dual-functional ATP-binding cassette transporters export antimicrobial or quorum signaling peptides in Gram-positive bacteria. Their substrates contain a leader sequence that is excised by an N-terminal peptidase C39 domain at a double Gly motif....
Article
Full-text available
N-Acetylgalactosamine (GalNAc) α-O-linked to l-threonine (Thr) (Tn antigen) and several mimics of this Tn antigen have been synthesized to explore the impact of the underlying amino acid in the presentation mode of the carbohydrate moiety. The structural changes introduced in the Tn antigen mimics involve the replacement of the natural underlying T...
Article
There is considerable interest in the development of chemical methods for the precise, site-selective modification of antibodies for therapeutic applications. In this protocol, we describe a strategy for the irreversible and selective modification of cysteine residues on antibodies, using functionalized carbonylacrylic reagents. This protocol is ba...
Article
A one-pot, high-yield procedure for synthesizing lanthionine-containing peptides was developed. It relies on the S-alkylation of cysteine-containing peptides with chiral cyclic sulfamidates. The key feature of this approach is the use of mild reaction conditions (only activated molecular sieves are employed as the catalyst), leading to good chemose...
Article
Full-text available
Photo‐activated drugs provide an opportunity to improve efficacy alongside reducing side‐effects in the treatment of severe diseases, such as cancer. Herein, we describe a photoactivation decaging method of isobutylene‐caged thiols through a UV‐initiated thiol‐ene reaction. The method was demonstrated with an isobutylene‐caged cysteine, cyclic disu...
Article
Full-text available
Photo‐activated drugs provide an opportunity to improve efficacy alongside reducing side‐effects in the treatment of severe diseases, such as cancer. Herein, we describe a photoactivation decaging method of isobutylene‐caged thiols through a UV‐initiated thiol‐ene reaction. The method was demonstrated with an isobutylene‐caged cysteine, cyclic disu...
Article
Full-text available
Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, an inhibitor of viral entry, a therapeutic for cystic fibrosis, and a tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalani...
Poster
Full-text available
Leader peptide removal at a double glycine motif by a protease (LanT) is the final step in the biosynthesis of class II lanthipeptides. LanTs comprise of an N-terminal cysteine protease domain, a transmembrane domain and an ATP-binding cassette. A novel lanthipeptide biosynthetic gene cluster was found that encodes multiple precursor peptides with...
Article
Full-text available
The tumor-associated carbohydrate Tn antigens include two variants, αGalNAc-O-Thr and αGalNAc-O-Ser. In solution, they exhibit dissimilar shapes and dynamics and bind differently to the same protein receptor. Here, we demonstrate experimentally and theoretically that their conformational preferences in the gas phase are highly similar, revealing th...
Preprint
Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, inhibitor of viral entry, therapeutic for cystic fibrosis, and tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal...