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Abstract: Leishmaniasis is a neglected disease that affects around two million people every year. Current treatments are often highly toxic or prone to resistance, underscoring the urgent need for new therapeutic strategies. PROTACs may offer a promising alternative, as they can potentially mitigate both toxicity and resistance. However, very little is known about the ubiquitin–proteasome system (UPS) in Leishmania. Notably, only two E3 ligases containing a CULT domain have been identified so far, and none carrying a von Hippel–Lindau (VHL) domain─the classical E3 ligase used by clinically advanced PROTACs. In this work, we take an important step toward understanding the UPS in Leishmania, and we propose that in this organism the UbC4 E2 enzyme, rather than an E3, may be directly exploited to develop a PROTAC able to engage a protein of interest. Here, we report the biochemical and structural characterization of the Leishmania major ubiquitin-conjugating enzyme 4 (UbC4). Through a fragment screening campaign, we identified 10 fragments binding to distinct cavities on UbC4. Among these, five interact with the same noncatalytic pocket that is poorly conserved in humans, while one fragment binds near the catalytic cysteine. Using DeepFrag predictions and molecular docking, we explored fragment elongation strategies to enhance affinity for their respective binding sites, with the goal of guiding the development of E2-recruiting PROTACs or UPS inhibitors for the treatment of leishmaniasis.

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Abstract: The development of efficient and durable electrocatalysts for the formic acid oxidation reaction (FAOR) is central to the progress of direct formic acid fuel cells (DFAFCs). Here, we investigate how the synthesis sequence and reduction pathway influence the surface and electronic structure of PdAgNi(OH)2/C nanocomposites and, consequently, their FAOR performance in acidic media. Binary Pd/Ni(OH)2 catalysts with Pd/Ni(OH)2 mass ratios of 30:70, 50:50, and 70:30 were first screened, revealing 50:50 as the optimal composition. Partial substitution of Pd by Ag (Pd40Ag10 and Pd30Ag20 on Ni(OH)2(50)/C) was then combined with either sequential or simultaneous NaBH4-assisted reduction. Structural characterization by XRD, TEM, and XANES/EXAFS show that simultaneous coreduction tightens the Pd–Ag–Ni interfacial coupling, enhances Pd dispersion, and increases the contribution of Pd–O and Pd–Ni scattering paths, indicative of strong metal–oxide interactions. Electrochemical measurements demonstrate that the Pd30Ag20Ni(OH)2(50)/C catalyst prepared by simultaneous reduction exhibits the highest mass activity toward FAOR (6164 mA mgPd–1), a ca. 23-fold enhancement over commercial Pd/C, together with improved stability under potential cycling. These results demonstrate that controlling the synthesis sequence is an effective method for tuning the interfacial electronic structure of multicomponent Pd-based catalysts, providing practical guidelines for designing FAOR electrocatalysts for DFAFCs and related liquid-fuel energy conversion devices.

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Abstract: Candida glabrata is the second leading cause of mortality in immunocompromised patients hospitalized for invasive candidiasis (IC). Several drugs have been available to treat this disease for decades, such as polyenes, azoles, echinocandins, flucytosine, and, in critical cases, amphotericin B. However, these antifungals’ constant and routine use have led to the development of resistance mechanisms, making the design and development of new drugs indispensable. The first step for the design and subsequent synthesis of a new chemical molecule as a potential antifungal is the identification of new therapeutic targets. In that pathway, our working group has identified moonlight-like cell wall proteins (CWPs) in different Candida species that can act as potential antifungal targets. One of these moonlight-like CWPs is phosphoglycerate kinase (Pgk) from C. glabrata. Once Pgk was identified as a potential therapeutic target in different human pathogens, the first step to perform drug design against this moonlight-like CWP was the elucidation of the three-dimensional (3D) structure since the 3D structure is key to understanding the interactions between a drug candidate and its target at the molecular level. In the present work, we aimed to elucidate the 3D structure of C. glabrata Pgk. To elucidate the 3D structure of this protein, the recombinant protein was expressed, purified, and structurally resolved by means of a structural analysis by small-angle X-ray scattering (SAXS). Additionally, in order to evaluate its potential as a therapeutic target, we have performed molecular docking studies and enzymatic activity assays with pure Pgk using known antifungals amphotericin B, nystatin, and fluconazole and with the new plausible drugs, such as nilotinib and netupitant. Our results showed some similarities and differences with orthologous Pgk proteins from other organisms, which was expected since Pgk has been observed to have evolved in the kingdoms of life. Molecular docking studies showed that Pgk interacts with all of the compounds tested. In enzyme activity assays, a change in the kinetic parameter Km on the enzyme Pgk was observed in response to its interaction with nilotinib, netupitant, and amphotericin B. Thus, our results allow us to propose Pgk from C. glabrata as a possible therapeutic target against candidiasis. We consider it essential to design and develop new molecules specifically targeting this enzyme, which will contribute to a decrease in mortality associated with IC and improve the patient’s quality of life.

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Abstract: We report that self-supporting mesoporous platinum 3D nanowires with a single diamond (SD) morphology and a high specific surface area of 40.4 m2 g–1 demonstrated enhanced stability toward the oxygen reduction reaction (ORR). These were found to be superior to commercially available carbon-supported Pt nanoparticles (Pt/C). After 1000 potential cycles, there was a 21% loss in surface area for SD-Pt, as compared with a 40.3% loss for Pt/C with no reduction in their half-wave potential (measured at J = 3.0 mA cm–2), whereas the Pt/C catalyst showed a 11.9 mV decrease. Our findings revealed that our SD-Pt thin films also exhibited excellent ORR activity, which offers significant potential for their application as high-performance cathode materials in alkaline fuel cells.

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Abstract: The influence of surfactant, cross-linker, and initiator on the final structure and thermoresponse of poly(N-isopropylmethacrylamide) (pNIPMAM) microgels was evaluated. The goals were to control particle size (into the nanorange) and transition temperature (across the physiologically accessible range). The concentration of the reactants used in the synthesis was varied, except for the monomer, which was kept constant. The thermoresponsive suspensions formed were characterized by dynamic light scattering, small-angle X-ray scattering, atomic force microscopy, and rheology. Increasing surfactant, sodium dodecyl sulfate content, produced smaller microgels, as expected, into the nanorange and with greater internal entanglement, but with no change in phase transition temperature (LCST), which is contrary to previous reports. Increasing cross-linker, N,N-methylenebis acrylamide, content had no impact on particle size but reduced particle deformability and, again contrary to previous reports of decreases, progressively increased the LCST from 39 to 46 °C. The unusual LCST trends were confirmed using different rheological techniques. Initiator, potassium persulfate, content was found to weakly influence the outcomes. An optimized content was identified that provides functional nanogels in the 100 nm (swollen) size range with controlled LCST, just above physiological temperature. The study contributes chemistry-derived design rules for thermally responsive colloidal particles with physiologically accessible LCST for a variety of biomedical and soft robotics applications.