Damián Álvarez Paggi

National University of General San Martín | UNSAM · Centro de Rediseño e Ingeniería de Proteínas

Convalescent plasma (CP) treatment of coronavirus disease 2019 (COVID-19) has shown significant therapeutic effect when administered early (eg, Argentinian trial showing reduced hospitalization) but has in general been ineffective (eg, REMAP-CAP trial without improvement during hospitalization). To investigate whether the differences in CP used cou...

Respiratory syncytial virus (RSV) has a major role in respiratory infections in young infants around the world. However, substantial progress has been made in recent years in the field of RSV. A wide variety of observational studies and clinical trials published in the past decade provide a thorough idea of the health and economic burden of RSV dis...

As in most enveloped RNA viruses, the Respiratory Syncytial Virus Matrix (RSV-M) protein plays key roles in viral assembly and uncoating. It also plays non-structural roles related to transcription modulation through nucleo-cytoplasmic shuttling and nucleic acid binding ability. We dissected the structural and conformational changes underlying the...

Background: Precise determination of the causal chain that leads to community deaths in children in low- and middle-income countries is critical to estimating all causes of mortality accurately and to planning preemptive strategies for targeted allocation of resources to reduce this scourge. Methods: An active surveillance population-based study...

In 1967, two toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (FIRSV) in the United States died from enhanced RSV disease (ERD), a severe form of illness resulting from aberrant priming of the antiviral immune response during vaccination. Up to 80% of immunized children subsequently exposed to wild-type vir...

We reported cases of community mortality due to RSV in low settings of Buenos Aires, Argentina.

Background Many deaths in infants from low-middle income countries (LMICs) occur at home or upon arrival to health facilities. Although acute lower respiratory tract illness plays an important role in community mortality, the accuracy of mortality rates due to respiratory syncytial virus (RSV) remains unknown. Methods An active surveillance study...

Efforts to best protect the world from SARS-CoV-2 as variants emerge and despite limited vaccine supply are ongoing. One strategy that may maximize vaccine quantities and expedite immunization campaigns involves providing single mRNA vaccine doses to individuals with previous COVID-19. In this issue of the JCI two independent studies, Levi et al. a...

Background Bronchopulmonary dysplasia (BPD) affects 20-40% of very low birth weight infants (VLBW) who endure short and long-term limitations throughout their life. Experts have classified the disease based on oxygen and pressure exposure at different time points, on the continuum of disease progression, ignoring the rich respiratory and clinical h...

Background Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. Methods We conducted a randomized, double-blind, placebo-cont...

Background Therapies to interrupt progression of early COVID-19 remain elusive. Among them, convalescent plasma in hospitalized patients was unsuccessful, perhaps because antibody should be administered earlier. We advanced plasma infusions to the first 72 hours of symptoms to arrest COVID-19 progression. Methods A randomized, double-blind, placeb...

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus that can affect lung physiology encompassing a wide spectrum of severities, ranging from asymptomatic and mild symptoms to severe and fatal cases; the latter including massive neutrophil infiltration, stroke and multiple organ failure. Despite many recents findings, a clear mechanisti...

CuA centers perform efficient long-range electron transfer. The electronic structure of native CuA sites can be described by a double-potential well with a dominant σu* ground state in fast equilibrium with a less populated πu ground state. Here, we report a CuA mutant in which a lysine was introduced in the axial position. This results in a highly...

Background: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung ill...

Redox regulation in biology is largely operated by cysteine chemistry in response to a variety of cell environmental and intracellular stimuli. The high chemical reactivity of cysteines determines their conservation in functional roles, but their presence can also result in harmful oxidation limiting their general use by proteins. Papillomaviruses...

Here we investigated the effect of electrostatic interactions and of protein tyrosine nitration of mammalian cytochrome c on the dynamics of the so-called alkaline transition, a pH- and redox-triggered conformational change that implies replacement of the axial ligand Met80 by a Lys residue. Using a combination of electrochemical, time-resolved SER...

Among Mononegavirales, the Pneumovirus family stands out by its RNA polymerase processivity that relies on a transcription antiterminator, the M2-1 protein, which also plays a key role in viral particle assembly. Biophysical and structural evidence shows that this RNA-binding tetramer is strongly modulated by a CCCH Zn²⁺ binding motif. We show that...

Manganese(III) ortho N-substituted pyridylporphyrins (MnP) act as efficient antioxidants catalyzing superoxide dismutation and accelerating peroxynitrite reduction. Importantly, MnP can reach mitochondria offering protection against reactive species in different animal models of disease. In this scenario, we applied Resonance Raman (RR) spectroscop...

Manganese(III) cationic ortho N-substituted pyridylporphyrins (MnP) act as efficient antioxidants catalyzing superoxide dismutation and accelerating peroxynitrite reduction. Importantly, MnP can reach mitochondria thereby offer protection against reactive species in different animal models of disease. Although an LC-MS/MS-based method for MnP quant...

Copper sites in proteins are designed to perform either electron transfer or redox catalysis. Type 1 and CuA sites are electron transfer hubs bound to a rigid protein fold that prevents binding of exogenous ligands and side reactions. Here we report the engineering of two Type 1 sites by loop-directed mutagenesis within a CuA scaffold with unique e...

Manganese Porphyrins (MnPs) act as efficient catalytic antioxidants. They can reach mitochondria and confer pharmacological protection in pathologies related to an increase in oxidants formation, particularly peroxynitrite. However, a direct method to evaluate the uptake and redox state of MnPs in living cells has not been developed. In this work b...

Cytochrome c (cyt c) is a small soluble heme protein characterized by a relatively flexible structure, particularly in the ferric form, such that it is able to sample a broad conformational space. Depending on the specific conditions, interactions, and cellular localization, different conformations may be stabilized, which differ in structure, redo...

Manganese porphyrins (MnPs) can act as efficient catalytic antioxidants. MnPs can reach mitochondria and confer pharmacological protection in different models of disease where oxidants such as peroxynitrite participate. MnPs quantitation and subcellular distribution by LC-MS/MS has been reported; however, a direct method to evaluate their uptake an...

Manipulation of the partition function (Q) of the redox center CuA from cytochrome oxidase is attained by tuning the accessibility of a low lying alternative electronic ground state and by perturbation of the electrostatic potential through point mutations, loop engineering and pH variation. We report clear correlations of the entropic and enthalpi...

Manganese(III) cationic ortho N-substituted pyridylporhyrins (MnPs) act as efficient antioxidants catalyzing superoxide dismutation and accelerating peroxynitrite reduction. Importantly, MnPs reach mitochondria and protect them in different animal models of disease, furthermore, MnTnBuOE-2-PyP⁵⁺ is presently in Phase I/II clinical trial as a normal...

Cytochrome c (cyt c) is a cationic hemoprotein of ca. 100 amino acid residues that exhibits exceptional functional versatility. While its primary function is electron transfer in the respiratory chain, cyt c is also recognized as a key component of the intrinsic apoptotic pathway, the mitochondrial oxidative protein folding machinery and presumably...

The CuA site of cytochrome c oxidase is a redox hub that participates in rapid electron transfer at low driving forces with two redox cofactors in nearly perpendicular orientations. Spectroscopic and electrochemical characterizations performed on first and second-sphere mutants have allowed us to experimentally detect the reversible switching betwe...

The CuA center is a dinuclear copper site that serves as an optimized hub for long-range electron transfer in heme–copper terminal oxidases. Its electronic structure can be described in terms of a σu* ground-state wavefunction with an alternative, less populated ground state of πu symmetry, which is thermally accessible. It is now shown that second...

The CuA center is a dinuclear copper site that serves as an optimized hub for long-range electron transfer in heme–copper terminal oxidases. Its electronic structure can be described in terms of a σu* ground-state wavefunction with an alternative, less populated ground state of πu symmetry, which is thermally accessible. It is now shown that second...

In this overview we present recent combined electrochemical, spectroelectrochemical, spectroscopic and computational studies from our group on the electron transfer reactions of cytochrome c and of the primary electron acceptor of cytochrome c oxidase, the CuA site, in biomimetic complexes. Based on these results, we discuss how protein dynamics an...

Here we report a spectroscopic, electrochemical and computational study of cytochrome c showing that nitration of Tyr74 induces Tyr deprotonation, which is coupled to Met/Lys axial ligand exchange, and results in concomitant gain of peroxidatic activity at physiological pH.

Previous studies on engineered CuA centres have shown that one of the histidine ligands is protonated and dissociated from the metal site at physiological pH values, thus suggesting a role in regulating proton-coupled electron transfer of cytochrome c oxidases in vivo. Here we report that for native CuA such protonation does not take place at physi...

Non-exponential distance-dependence of the apparent electron transfer (ET) rate has been reported for a variety of redox proteins immobilized on biocompatible electrodes, thus posing a physicochemical challenge of possible physiological relevance. We have recently proposed that this behaviour may arise from the structural and dynamical complexity n...

We have employed a combination of protein film voltammetry, time-resolved vibrational spectroelectrochemistry and molecular dynamics simulations to evaluate the electron transfer reorganization free energy (λ) of cytochrome c (Cyt) in electrostatic complexes that mimic some basic features of protein-protein interactions. The results reveal the exis...

Electron transfer is the simplest chemical reaction and constitutes the basis of a large variety of biological processes, such as photosynthesis and cellular respiration. Nature has evolved specific proteins and cofactors for these functions. The mechanisms optimizing biological electron transfer have been matter of intense debate, such as the role...

Page 5774. Due to a production error, Figure 4 is incorrect in the published article. The correct figure is shown below.

Direct electron transfer (ET) of redox proteins immobilized on biomimetic or biocompatible electrodes represents an active field of fundamental and applied research. In this context, several groups have reported for a variety of proteins unexpected distance dependencies of the ET rate, whose origin remains largely speculative and controversial, but...

The heterogeneous electron-transfer (ET) reaction of cytochrome c (Cyt-c) electrostatically or covalently immobilized on electrodes coated with self-assembled monolayers (SAMs) of omega-functionalized alkanethiols is analyzed by surface-enhanced resonance Raman (SERR) spectroscopy and molecular dynamics (MD) simulations. Electrostatically bound Cyt...

Cytochrome c (Cyt) is a small soluble heme protein with a hexacoordinated heme and functions as an electron shuttle in the mitochondria and in early events of apoptosis when released to the cytoplasm. Using molecular dynamics simulations, we show here that biologically relevant electric fields induce an increased mobility and structural distortion...

In this paper we present a combined experimental and theoretical study of the heterogeneous electron transfer reaction of cytochrome c electrostatically adsorbed on metal electrodes coated with monolayers of 6-mercaptohexanoic acid. Molecular dynamics simulations and pathways calculations show that adsorption of the protein leads to a broad distrib...