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Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells' response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells.
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Trimethoprim (TMP), as a widely used chemotherapeutic antibiotic agent, has caused potential risks to the aquatic environment. In this study, magnetic Co-doped Fe3O4/α-FeOOH was fabricated by a facile one-step ageing method and used for activation of peroxymonosulfate (PMS) in TMP degradation. It was found that low catalyst (0.5 g/L) and PMS addition (0.2 mM) led to the high degradation efficiency of TMP (97.2%, kobs = 0.11211 min-1) over a wide range of pH. The oxidation of active radical (SO4·-) and non-radical singlet oxygen (1O2) co-acted on TMP degradation. Besides, PMS was activated through the cycles between Co(II)/Co(III) and Fe(II)/Fe(III). Fifteen degradation intermediates of TMP were identified by LC-MS, and three possible degradation pathways including hydroxylation, demethylation, and cleavage were proposed. The recovered catalysts exhibited high stability and reusability, maintaining 80% TMP removal efficiency with inappreciable metal leaching (0.012 mg/L of Co, 0.113 mg/L of Fe) after six cycles. Besides, the Co-Fe3O4/α-FeOOH/PMS system was highly tolerant to inorganic anions and actual water bodies (river water, lake water, tap water, and sewage plant effluent). Overall, this work provided a promising way to the potential application of Fe-based binary metal oxide for PMS activation.
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Compuestos Férricos , Trimetoprim , Peróxidos , AguaRESUMEN
As SARS-CoV-2 Omicron and other variants of concern (VOCs) continue spreading worldwide, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with potency against diverse VOCs including Omicron subvariants BA.1, BA.2 and BA.4/5, SARS-CoV-1, and major sarbecoviruses. Crystal structure analysis of one representative nanobody, 3-2A2-4, discovers a highly conserved epitope located between the cryptic and the outer face of the receptor binding domain (RBD), distinctive from the receptor ACE2 binding site. Cryo-EM and biochemical evaluation reveal that 3-2A2-4 interferes structural alteration of RBD required for ACE2 binding. Passive delivery of 3-2A2-4 protects K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. Identification of these unique nanobodies will inform the development of next generation antibody therapies and design of pan-sarbecovirus vaccines.
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COVID-19 , Camélidos del Nuevo Mundo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Anticuerpos de Dominio Único , Animales , Ratones , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , COVID-19/prevención & control , Anticuerpos Neutralizantes , Glicoproteína de la Espiga del Coronavirus , Anticuerpos AntiviralesRESUMEN
Striking number of mutations found in the spike protein of recently emerged SARS-CoV-2 Omicron subvariants BA.1, BA.2, BA.3 and BA.4/5 has raised serious concerns regarding the escape from current antibody therapies and vaccine protection. Here, we conducted comprehensive analysis on the extent of two major Omicron lineages BA.1/BA.1.1 and BA.2 to escape neutralization from the therapeutic antibodies approved by the regulatory authorities and convalescent plasma from SARS-CoV-2 patients infected during initial wave of pandemic in early 2020. We showed that Omicron BA.1/BA.1.1 were the most resistant in both magnitude and breadth against antibodies and convalescent plasma, followed by Beta, BA.2, Gamma, Delta and Alpha. While the majority of therapeutic antibodies lost binding and neutralization to Omicron variants, BRII combo (BRII-196 + BRII-198), S309, and AZ combo (COV2-2196 + COV2-2130) maintained neutralization despite of reduction due to either conserved epitope or combinational effect between the two designated antibodies. A single intraperitoneal injection of BRII combo as a prophylactic treatment protected animals from Omicron infection. Treated animals manifested normal body weight, survived infection up to 14 days, undetectable levels of infectious viruses in the lungs, and reduced lung pathology compared to the controls. Analyzing ACE2 from diverse host species showed that Omicron variants acquired ability to use mouse ACE2 for entry. These results demonstrate major antigenic shifts and potentially broadening the host range of two major Omicron lineages BA.1/BA.1.1 and BA.2, posing serious challenges to current antibody therapies and vaccine protection as well as increasing danger of spillover into the wildlife.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , Animales , Animales Salvajes , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , COVID-19/terapia , Inmunización Pasiva , Ratones , SARS-CoV-2/genética , Sueroterapia para COVID-19RESUMEN
SignificanceSARS-CoV-2 continues to evolve through emerging variants, more frequently observed with higher transmissibility. Despite the wide application of vaccines and antibodies, the selection pressure on the Spike protein may lead to further evolution of variants that include mutations that can evade immune response. To catch up with the virus's evolution, we introduced a deep learning approach to redesign the complementarity-determining regions (CDRs) to target multiple virus variants and obtained an antibody that broadly neutralizes SARS-CoV-2 variants.
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Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/farmacología , Vacunas contra la COVID-19/inmunología , Regiones Determinantes de Complementariedad , Aprendizaje Profundo , Epítopos/inmunología , Humanos , Inmunoterapia/métodos , Pruebas de Neutralización/métodos , Dominios Proteicos , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
The latest research has indicated that anti-tumor agents with COX-2 inhibitory activity may benefit their anti-tumor efficiency. A series of sclerotiorin derivatives have been synthesized and screened for their cytotoxic activity against human lung cancer cells A549, breast cancer cells MDA-MB-435 using the MTT method. Among them, compounds 3, 7, 12, 13, 15, 17 showed good cytotoxic activity with IC50 values of 6.39, 9.20, 9.76, 7.75, 9.08, and 8.18 µM, respectively. In addition, all compounds were tested in vitro the COX-2 inhibitory activity. The results disclosed compounds 7, 13, 25 and sclerotiorin showed moderate to good COX-2 inhibition with the inhibitory ratios of 58.7%, 51.1%, 66.1% and 56.1%, respectively. Notably, compound 3 displayed a comparable inhibition ratio (70.6%) to the positive control indomethacin (78.9%). Furthermore, molecular docking was used to rationalize the potential of the sclerotiorin derivatives as COX2 inhibitory agents by predicting their binding energy, binding modes and optimal orientation at the active site of the COX-2. Additionally, the structure-activity relationships (SARS) have been addressed.
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Antineoplásicos/farmacología , Benzopiranos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Neoplasias/tratamiento farmacológico , Células A549 , Antineoplásicos/síntesis química , Benzopiranos/síntesis química , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Molecular , Neoplasias/patología , Relación Estructura-ActividadRESUMEN
Metal halide perovskite quantum dots (PQDs), with excellent optical properties and spectacular characteristics of direct and tunable bandgaps, strong light-absorption coefficients, high defect tolerance, and low nonradiative recombination rates, are highly attractive for modern optoelectronic devices. However, the stability issue of PQDs remains a critical challenge of this newly emerged material despite the recent rapid progress. Here, the encapsulation strategies to improve the stability of PQDs are comprehensively reviewed. A special emphasis is put on the effects of encapsulation, ranging from the improvement of chemical stability, to the inhibition of light-induced decomposition, to the enhancement of thermal stability. Particular attention is devoted to summarizing the encapsulation approaches, including the sol-gel method, the template method, physical blending, and microencapsulation. The selection principles of encapsulation materials, including the rigid lattice or porous structure of inorganic compounds, the low penetration rate of oxygen or water, as well as the swelling-deswelling process of polymers, are addressed systematically. Special interest is put on the applications of the encapsulated PQDs with improved stability in white light-emitting diodes, lasers, and biological applications. Finally, the main challenges in encapsulating PQDs and further investigation directions are discussed for future research to promote the development of stable metal halide perovskite materials.