Didemnin B . Specific Interaction Between eEF1A and HIV RT Is Critical for HIV-1 Reverse Transcription and a Potential Anti-HIV Target .

P.J.: Es del 2015 ... Pero es el resultado de  I+D en el que Ya se Demuestra su Actividad AntiViral ... Frente al HIV - 1 .

Abstract

Reverse transcription is the central defining feature of HIV-1 replication. We previously reported that the cellular eukaryotic elongation factor 1 (eEF1) complex associates with the HIV-1 reverse transcription complex (RTC) and the association is important for late steps of reverse transcription. Here we show that association between the eEF1 and RTC complexes occurs by a strong and direct interaction between the subunit eEF1A and reverse transcriptase (RT). Using biolayer interferometry and co-immunoprecipitation (co-IP) assays, we show that association between the eEF1 and RTC complexes occurs by a strong (KD ~3-4 nM) and direct interaction between eEF1A and reverse transcriptase (RT). Biolayer interferometry analysis of cell lysates with titrated levels of eEF1A indicates it is a predominant cellular RT binding protein. Both the RT thumb and connection domains are required for interaction with eEF1A. A single amino acid mutation, W252A, within the thumb domain impaired co-IP between eEF1A and RT, and also significantly reduced the efficiency of late reverse transcription and virus replication when incorporated into infectious HIV-1. Molecular modeling analysis indicated that interaction between W252 and L303 are important for RT structure, and their mutation to alanine did not impair heterodimerisation, but negatively impacted interaction with eEF1A. Didemnin B, which specifically binds eEF1A, potently inhibited HIV-1 reverse transcription by greater than 2 logs at subnanomolar concentrations, especially affecting reverse transcription late DNA synthesis. Analysis showed reduced levels of RTCs from HIV-1-infected HEK293T treated with didemnin B compared to untreated cells. Interestingly, HIV-1 with a W252A RT mutation was resistant to didemnin B negative effects showing that didemnin B affects HIV-1 by targeting the RT-eEF1A interaction. The combined evidence indicates a direct interaction between eEF1A and RT is crucial for HIV reverse transcription and replication, and the RT-eEF1A interaction is a potential drug target.

Covid19 . Los Turistas Comienzan a Cancelar sus Reservas. Los Rebrotes Amenazan la Recuperación del Turismo Nacional .

Magaluf todo incluido por 100 euros . Turismo le llaman . Más bien parece ... Ve a España y haz lo que te de la gana ...

En una búsqueda por Internet se pueden encontrar suculentos paquetes de 'todo incluido' para este verano. El destino de Magaluf es uno de los más ofertados para el mercado británico, que por alrededor de 100 euros la noche pueden disfrutar de una estancia en un hotel de la zona y la playa. Gastos a parte la fiesta fuera del establecimiento.

Tubulin Maytansine Site Binding Ligands and Their Applications as MTAs and ADCs for Cancer Therapy .

Background: Microtubule Targeting Agents (MTAs) represent the most successful anticancer drugs for cancer chemotherapy. Through interfering with the tubulin polymerization and depolymerization dynamics, MTAs influence intracellular transport and cell signal pathways, inhibit cell mitosis and cell proliferation, and induce cell apoptosis and death. The tubulin maytansine site binding agents are natural or nature-derived products that represent one type of the MTAs that inhibit tubulin polymerization and exhibit potent antitumor activity both in vitro and in vivo. They are used as Antibody-Drug Conjugates (ADCs) in cancer chemotherapy.

Methods: Using SciFinder® as a tool, the publications about maytansine, its derivatives, maytansine binding site, maytansine site binding agents and their applications as MTAs for cancer therapy were surveyed with an exclusion on those published as patents. The latest progresses in clinical trials were obtained from the clinical trial web.

Results: This article presents an introduction about MTAs, maytansine, maytansine binding site and its ligands, the applications of these ligands as MTAs and ADCs in cancer therapy. Conclusion: The maytansine site binding agents are powerful MTAs for cancer chemotherapy.

The maytansine site ligands-based ADCs are used in clinic or under clinical trials as cancer targeted therapy to improve their selectivity and to reduce their side effects. Further improvements in the delivery efficiency of the ADCs will benefit the patients in cancer targeted therapy.

Keywords: Microtubule targeting agents, maytansine binding site, rhizoxin, Plocabulin, antibody-drug conjugates, trastuzumab emtansine.

Covid19 . Ya son más de 120 los Rebrotes de Coronavirus Activos en España. Mapa de los Rebrotes del Coronavirus en España hoy martes 14 de julio de 2020 .

Las Biotecnológicas Chinas Desatan la Fiebre Inversora .

Revés para Roche: Tecentriq Falla en un Ensayo en Mujeres con Cáncer de Ovario . El Medicamento de la Compañía Farmacéutica No Aumentó la Supervivencia sin que la Enfermedad Progresara.