Assembly path dependence of telomeric DNA compaction by TRF1, TIN2, and SA1.

Telomeres, complexes of DNA and proteins, protect ends of linear chromosomes. In humans, the two shelterin proteins TRF1 and TIN2, along with cohesin subunit SA1, were proposed to mediate telomere cohesion. Although the ability of the TRF1-TIN2 and TRF1-SA1 systems to compact telomeric DNA by DNA-DNA bridging has been reported, the function of the full ternary TRF1-TIN2-SA1 system has not been explored in detail. Here, we quantify the compaction of nanochannel-stretched DNA by the ternary system, as well as its constituents, and obtain estimates of the relative impact of its constituents and their interactions. We find that TRF1, TIN2, and SA1 work synergistically to cause a compaction of the DNA substrate, and that maximal compaction occurs if all three proteins are present. By altering the sequence with which DNA substrates are exposed to proteins, we establish that compaction by TRF1 and TIN2 can proceed through binding of TRF1 to DNA, followed by compaction as TIN2 recognizes the previously bound TRF1. We further establish that SA1 alone can also lead to a compaction, and that compaction in a combined system of all three proteins can be understood as an additive effect of TRF1-TIN2 and SA1-based compaction. Atomic force microscopy of intermolecular aggregation confirms that a combination of TRF1, TIN2, and SA1 together drive strong intermolecular aggregation as it would be required during chromosome cohesion.

SERDs: a case study in targeted protein degradation.

Endocrine therapies for breast cancer target ERα which is found in more than 70% of breast cancers. Unfortunately, endocrine resistance typically occurs, in which case Selective Estrogen Receptor Degraders (SERDs) represent the last line of treatment for metastatic breast cancer patients. Fulvestrant, the only currently approved SERD and one of the first targeted protein degradation therapies, presents poor drug-like properties which has led to the development of a new generation of oral SERDs. This review summarizes recent progress in the evolution of SERDs, focusing on clinical candidates and their degradation motifs within the broader context of targeted protein degradation therapies.

Boron-Promoted Deprotonative Conjugate Addition: Geminal Diborons as Soft Pronucleophiles and Acyl Anion Equivalents.

Conjugate addition of α-boron-stabilized carbanions is an underexplored reaction modality. Existing methods require deborylation of geminal di-/triboryl alkanes and/or the presence of additional activating groups. We report the 1,4-addition of α,α-diboryl carbanions generated via deprotonation of the corresponding geminal diborons. The methodology provided a general route to highly substituted and synthetically useful γ,γ-diboryl ketones. The development of geminal diborons as soft pronucleophiles also enabled their use as acyl anion equivalents via a one-pot tandem conjugate addition-oxidation sequence.

Acrylic boronate: a multifunctional C3 building block for catalytic synthesis of rare organoborons and chemoselective heterobifunctional ligations.

A novel C3 acylboron building block; acrylic boronate was successfully prepared and its versatility for catalytic synthesis of several previously inaccessible organoborons is described. Cross-metathesis and Pd-catalyzed coupling of acrylic boronate enabled two complementary routes to highly functionalized α,ß-unsaturated acylborons and two new types of conjugated borylated products: α,ß,γ,δ-unsaturated and bis-α,ß unsaturated acylborons. The synthetic application of α,ß-unsaturated acylborons was demonstrated for the first time, thereby providing a general and highly regioselective route to medicinally important 3-boryl pyrazoles. Acrylic boronate also provided a unique bis-electrophilic platform for rapid and chemoselective labeling of cysteines with acylboron tags which are potentially useful for site-selective functionalization and orthogonal ligation of proteins.

α-Hydroxy boron-enabled regioselective access to bifunctional halo-boryl alicyclic ethers and α-halo borons.

α-Hydroxy borons are an underutilized class of compounds and their only previous application involved oxidation into acylborons. Herein, we describe the synthesis of functionalized olefinic α-hydroxy borons and their utility to enable a novel and regioselective route to hitherto unknown bifunctional halo-boryl tetrahydrofurans/tetrahydropyrans and α-halo MIDA boronates. The orthogonally functionalized alicyclic ethers provided a building block-based approach for diversification of the tetrahydrofuran core.

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs).

Estrogen receptor-alpha (ERα) is the target of endocrine therapies for the treatment of more than 70 % of ERα-positive breast cancers. Selective estrogen receptor degraders (SERDs) antagonize estrogen binding and target the receptor for degradation, representing the last line of treatment for resistant metastatic breast cancer patients. However, the clinical efficacy of the lone clinically approved SERD (Fulvestrant) is limited by its poor oral bioavailability. Recently, several analogues of GW5638, an acrylic acid-based ERα ligand developed by Glaxo Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure-activity relationships, binding interactions and pharmacokinetic properties of these compounds.

A modular and concise approach to MIDA acylboronates via chemoselective oxidation of unsymmetrical geminal diborylalkanes: unlocking access to a novel class of acylborons.

Acylboronates represent a very intriguing and rare class of organoboronates. Synthesis of these compounds from readily available substrates under mild conditions and access to novel classes of acylborons has been challenging. We report a novel and concise route to various MIDA acylboronates from terminal alkynes/alkenes or vinyl boronic esters using unsymmetrical geminal diborylalkanes as key intermediates. The high modularity and mild conditions of this strategy allowed a facile access to acylboronates possessing aliphatic, aromatic as well as the rarer heteroaromatic, alkynyl and α,ß-unsaturated scaffolds. To the best of our knowledge, this is the first report of chemoselective oxidation of geminal diborons as well as synthesis of an α,ß-unsaturated acylboronate.

New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons.

An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.

Distribution dynamics of recombinant Lactobacillus in the gastrointestinal tract of neonatal rats.

One approach to deliver therapeutic agents, especially proteins, to the gastro-intestinal (GI) tract is to use commensal bacteria as a carrier. Genus Lactobacillus is an attractive candidate for use in this approach. However, a system for expressing exogenous proteins at a high level has been lacking in Lactobacillus. Moreover, it will be necessary to introduce the recombinant Lactobacillus into the GI tract, ideally by oral administration. Whether orally administered Lactobacillus can reach and reside in the GI tract has not been explored in neonates. In this study, we have examined these issues in neonatal rats. To achieve a high level of protein expression in Lactobacillus, we tested the impact of three promoters and two backbones on protein expression levels using mRFP1, a red fluorescent protein, as a reporter. We found that a combination of an L-lactate dehydrogenase (ldhL) promoter of Lactobacillus sakei with a backbone from pLEM415 yielded the highest level of reporter expression. When this construct was used to transform Lactobacillus casei, Lactobacillus delbrueckii and Lactobacillus acidophilus, high levels of mRFP1 were detected in all these species and colonies of transformed Lactobacillus appeared pink under visible light. To test whether orally administered Lactobacillus can be retained in the GI tract of neonates, we fed the recombinant Lactobacillus casei to neonatal rats. We found that about 3% of the bacteria were retained in the GI tract of the rats at 24 h after oral feeding with more recombinant Lactobacillus in the stomach and small intestine than in the cecum and colon. No mortality was observed throughout this study with Lactobacillus. In contrast, all neonatal rats died within 24 hours after fed with transformed E. coli. Taken together, our results indicate that Lactobacillus has the potential to be used as a vehicle for the delivery of therapeutic agents to neonates.

Promoción de la Salud y los Derechos Sexuales y Reproductivos y prevención del VIH/sida en jóvenes de sectores populares a través del uso de las Tecnologías de la Información y la Comunicación / Promotion of Sexual and Reproductive Health and rights and HIV / AIDS prevention among youth in low-income areas through the use of Information and Communication Technologies ICT

Se presentan los avances de un proyecto de investigación-acción orientado al desarrollo de una estrategia innovadora para la prevención del VIH/sida y la promoción de la Salud y los Derechos Sexuales y Reproductivos (SDSR) en población joven, a través del aprendizaje y el uso de las Tecnologías de la Información y la Comunicación (TIC). La iniciativa resulta de la adaptación en Argentina del proyecto Punto J liderado por el IES (Instituto de Educación y Salud) en Perú, el cual propone la creación de portales Web en 7 paises de la región, y el establecimiento de una Red Latinoamericana de Portales Juveniles. La transferencia se desarrolló por etapas: en un primer momento un equipo conformado por técnicos y promotores juveniles que trabajan en alianza con Fundación Huésped participó de una capacitación en TIC y de la estrategia Punto J, para poder replicarla en Argentina. Luego se transfirieron los contenidos a un grupo de jóvenes multiplicadores, adaptándolos a la realidad local. En este artículo se presentará el diagnóstico que sustenta la estrategia en la Argentina, las particularidades de la transferencia en nuestro país, el enfoque de trabajo, las lecciones aprendidas, los resultados obtenidos y las reflexiones acerca de la experiencia de esta novedosa iniciativa.

The paper presents the advances of a proyect of investigation-action addressing the development of an innovative strategy for the prevention of HIV/AIDS and promotion of Sexual and Reproductive Health and Rights (SRHR) among youth, through the learning and use of ICTs. The initiative is the product of the adaptation in Argentina of the proyect "Punto J", led by the IEH (Institute for Education and Heath), in Peru, an initiative that proposes the creation of web portals in 7 countries in the region and the establishment of a Latin American network of youth portals. The transference was developed in promoters who worked in alliance with Fundacion Huesped participated in training in ICT and the "Punto J" strategy, to be able to replicate this initiative in Argentina. Later, the ideas of this training were adapted to the local situation and transferred to a group of youth multipliers. This paper will present the results that support the strategy in Argentina, the particularities of the transference in our country, the focus of work, lessons learned, obtained results, and reflextions regarding the experience of this novel initiative.