Discovery of Highly Potent Small Molecule Pan-Coronavirus Fusion Inhibitors.

The unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, and its highly transmissible variants, led to massive human suffering, death, and economic devastation worldwide. Recently, antibody-evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. Therefore, the continued development of novel drugs with pan-coronavirus inhibition is critical to treat and prevent infection of COVID-19 and any new pandemics that may emerge. We report the discovery of several highly potent small-molecule inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI > 900), suggesting its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron), and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron), SARS-CoV-1, and MERS-CoV by plaque reduction in Calu-3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.

Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists.

As part of our effort to discover drugs that target HIV-1 entry, we report the antiviral activity and crystal structures of two novel inhibitors in a complex with a gp120 core. NBD-14204 showed similar antiviral activity against all the clinical isolates tested. The IC50 values were in the range of 0.24-0.9 µM with an overall mean of 0.47 ± 0.03 µM, showing slightly better activity against the clinical isolates than against the lab-adapted HIV-1HXB2 (IC50 = 0.96 ± 0.1 µM). Moreover, the antiviral activity of NBD-14208 was less consistent, showing a wider range of IC50 values (0.66-5.7 µM) with an overall mean of 3 ± 0.25 µM and better activity against subtypes B and D (Mean IC50 2.2-2.5 µM) than the A, C and Rec viruses (Mean IC50 2.9-3.9 µM). SI of NBD-14204 was about 10-fold higher than NBD-14208, making it a better lead compound for further optimization. In addition, we tested these compounds against S375Y and S375H mutants of gp120, which occurred in some clades and observed these to be sensitive to NBD-14204 and NBD-14208. These inhibitors also showed modest activity against HIV-1 reverse transcriptase. Furthermore, we determined the crystal structures of both inhibitors in complexes with gp120 cores. As expected, both NBD-14204 and NBD-14208 bind primarily within the Phe43 cavity. It is noteworthy that the electron density of the thiazole ring in both structures was poorly defined due to the flexibility of this scaffold, suggesting that these compounds maintain substantial entropy, even when bound to the Phe43 cavity.

Leites e seus substitutos de origem vegetal: avaliação e comparação da qualidade nutricional de seus rótulos / Milk and its vegetable substitutes: evaluation and comparison of nutritional quality of its labels

Leite é fonte importante de proteínas de alto valor biológico, vitaminas e minerais, porém, questões de alergia ou intolerância e um estilo de vida vegano ou vegetariano, têm levado à substituição por bebidas à base de vegetais. avaliar se a substituição é pertinente, este trabalho comparou os rótulos dos leites de origem animal e as bebidas vegetais disponíveis nos principais supermercados da Grande Vitória, ES. Foram avaliadas 56 embalagens de leite UHT (ultra high temperature) de vaca e de cabra, nas suas diferentes versões, e 41 de bebidas vegetais de amendoim, amêndoas, arroz, aveia, castanhas, coco, espelta, nuts e soja. As bebidas vegetais apresentaram, em geral, presença de fibras, maior teor de ácidos graxos insaturados e menor teor de sódio. Os leites se destacaram pela presença de colesterol, maior aporte proteico, de cálcio e das vitaminas A e D. As bebidas vegetais também apresentaram maiores quantidades de carboidratos e valor calórico. Sendo assim, se não há restrições para o consumidor, seja por questões de saúde, cultura ou hábito, a substituição de leite por bebidas vegetais não é equivalente. No entanto, o consumo de leites integrais deve ser equilibrado devido seu elevado teor de gorduras saturadas e de sódio. (AU)

Milk is an important source of high biological value proteins, vitamins and minerals, however, allergy or ntolerance issues, and a vegan or vegetarian lifestyle, have led its replacement by vegetables-based beverages. To evaluate weather this substitution is relevant; this study compared the labels of animal origin milk and the vegetable beverage available in the main supermarkets of Greater Vitória, ES. Fifty-six packages of cow and goat UHT milks, in their diferent versions, and 41 packages of vegetable beverages of peanuts, almonds, rice, oats, nuts, coconut, spelt, walnuts and soybeans were evaluated.The vegetable beverages presented, in general, the presence of fibers, higher content of unsaturated fatty acids and lower sodium content. Milks stood out due to the presence of cholesterol, higher protein intake, calcium and vitamins and D.Vegetable beverages also presented higher amount of carbohydrates and higher caloric value. Therefore, if there is no restriction, whether for health, culture or habit reasons, it is not equivalent to replace milks vegetable beverages.However, the consumption of whole milk should be balanced due to its high content of saturated fats and sodium. (AU)