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Indian Journal of Pharmacology 2020
Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antiviral Agents; Dexamethasone; Drug Approval; Legislation, Drug; Pandemics; COVID-19 Drug Treatment
PubMed: 33666185
DOI: 10.4103/ijp.ijp_32_21 -
The Journal of Antibiotics Jun 2019Adenylate-forming enzymes are a mechanistic superfamily that are involved in diverse biochemical pathways. They catalyze ATP-dependent activation of carboxylic acid... (Review)
Review
Adenylate-forming enzymes are a mechanistic superfamily that are involved in diverse biochemical pathways. They catalyze ATP-dependent activation of carboxylic acid substrates as reactive acyl adenylate (acyl-AMP) intermediates and subsequent coupling to various nucleophiles to generate ester, thioester, and amide products. Inspired by natural products, acyl sulfonyladenosines (acyl-AMS) that mimic the tightly bound acyl-AMP reaction intermediates have been developed as potent inhibitors of adenylate-forming enzymes. This simple yet powerful inhibitor design platform has provided a wide range of biological probes as well as several therapeutic lead compounds. Herein, we provide an overview of the nine structural classes of adenylate-forming enzymes and examples of acyl-AMS inhibitors that have been developed for each.
Topics: Adenosine Monophosphate; Drug Design; Enzyme Inhibitors; Ligases; Models, Molecular; Protein Conformation
PubMed: 30982830
DOI: 10.1038/s41429-019-0171-2 -
Biochemical and Biophysical Research... Jan 2021Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global pandemic. Although great efforts... (Review)
Review
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global pandemic. Although great efforts have been made to develop effective therapeutic interventions, only the nucleotide analog remdesivir was approved for emergency use against COVID-19. Remdesivir targets the RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral RNA replication and a promising drug target for COVID-19. Recently, several structures of RdRp in complex with substrate RNA and remdesivir were reported, providing insights into the mechanisms of RNA recognition by RdRp. These structures also reveal the mechanism of RdRp inhibition by nucleotide inhibitors and offer a molecular template for the development of RdRp-targeting drugs. This review discusses the recognition mechanism of RNA and nucleotide inhibitor by RdRp, and its implication in drug discovery.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Catalytic Domain; Coronavirus RNA-Dependent RNA Polymerase; Drug Discovery; Humans; Nucleic Acid Synthesis Inhibitors; Protein Conformation; RNA, Viral; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 32943188
DOI: 10.1016/j.bbrc.2020.08.116 -
Translational Psychiatry Dec 2022Repeated cocaine exposure causes compensatory neuroadaptations in neurons in the nucleus accumbens (NAc), a region that mediates reinforcing effects of drugs. Previous...
Repeated cocaine exposure causes compensatory neuroadaptations in neurons in the nucleus accumbens (NAc), a region that mediates reinforcing effects of drugs. Previous studies suggested a role for adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor, in modulating neuronal morphology and membrane excitability. However, the potential involvement of AMPK in cocaine use disorder is still unclear. The present study employed a cocaine self-administration model in rats to investigate the effect of AMPK and its target cyclic adenosine monophosphate response element binding protein-regulated transcriptional co-activator 1 (CRTC1) on cocaine reinforcement and the motivation for cocaine. We found that intravenous cocaine self-administration significantly decreased AMPK activity in the NAc shell (NAcsh), which persisted for at least 7 days of withdrawal. Cocaine reinforcement, reflected by self-administration behavior, was significantly prevented or enhanced by augmenting or suppressing AMPK activity pharmacologically and genetically, respectively. No difference in sucrose self-administration behavior was found after the same manipulations. The inhibition of AMPK activity in the NAcsh also increased the motivation for cocaine in progressive-ratio schedules of reinforcement, whereas the activation of AMPK had no effect. The knockdown of CRTC1 in the NAcsh significantly impaired cocaine reinforcement, which was rescued by pharmacologically increasing AMPK activity. Altogether, these results indicate that AMPK in the NAcsh is critical for cocaine reinforcement, possibly via the regulation of CRTC1 signaling. These findings may help reveal potential therapeutic targets and have important implications for the treatment of cocaine use disorder and relapse.
Topics: Rats; Animals; Cocaine; AMP-Activated Protein Kinases; Rats, Sprague-Dawley; Reinforcement, Psychology; Transcription Factors; Adenosine Monophosphate; Nucleus Accumbens; Self Administration
PubMed: 36587026
DOI: 10.1038/s41398-022-02299-w -
Clinical and Translational Science Apr 2022
Topics: Adenosine Monophosphate; Alanine; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance; Product Surveillance, Postmarketing
PubMed: 35303401
DOI: 10.1111/cts.13261 -
Pharmacology 2021The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of COVID-19 pandemic, resulted in significant harm to the affected countries in every... (Review)
Review
BACKGROUND
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of COVID-19 pandemic, resulted in significant harm to the affected countries in every aspect of life. The virus infected over 139 million patients and resulted in over 2.9 million deaths until April 16, 2021. New variants of this virus were identified that spread rapidly worldwide.
SUMMARY
Remdesivir, a prodrug of adenosine nucleotide analog, is an antiviral with a broad spectrum of activity that was tested on SARS and Middle East respiratory syndrome infections. In vitro studies conducted on SARS-CoV-2 revealed that remdesivir inhibited viral replication with high selectivity index in cell cultures. In vivo studies showed that remdesivir reduced viral load in bronchoalveolar lavage fluid and attenuated pulmonary infiltrates in infected animals. Further, remdesivir showed promising results in terms of clinical improvement, shortening the recovery time, mortality rate, and the duration of oxygen need, despite that some clinical trials did not reveal significant effect on remdesivir use. Several studies showed positive results of remdesivir against the new variants. Key Messages: Remdesivir showed a promising beneficial effect against new variants of SARS-CoV-2, but more clinical evidence is needed to confirm this effect.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; COVID-19; Humans; Pandemics; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34515227
DOI: 10.1159/000518440 -
ELife Mar 2014Cells dying by apoptosis can trigger an anti-inflammatory gene response in other cells by releasing a compound called adenosine monophosphate.
Cells dying by apoptosis can trigger an anti-inflammatory gene response in other cells by releasing a compound called adenosine monophosphate.
Topics: Adenosine Monophosphate; Animals; Apoptosis; Immune Tolerance
PubMed: 24668174
DOI: 10.7554/eLife.02583 -
Biomedical Papers of the Medical... Mar 2022By December 2019, humanity was challenged by a new infectious respiratory disease named coronavirus disease of 2019 or COVID-19. This is a viral infection based on the... (Review)
Review
By December 2019, humanity was challenged by a new infectious respiratory disease named coronavirus disease of 2019 or COVID-19. This is a viral infection based on the presence of the previously non-problematic coronavirus with assigned number 2. This virus causes severe acute respiratory distress and is known now as SARS-CoV2. Since SARS-CoV2 is an RNA virus, remdesivir and favipiravir, both broad-spectrum RNA polymerase inhibitors, were repurposed for treating COVID-19 patients. Remdesivir and favipiravir are antimetabolites, and they are structurally related to the naturally occurring structural elements of RNA. Both agents are prodrugs and must be activated intracellularly to exert their effects through numerous and different mechanisms of action. Efforts have been exerted to determine their efficacy and safety against COVID-19 through clinical trials. Clinical trials have shown an association of remdesivir with increased frequency of adverse effects (in comparison to favipiravir). Nevertheless, the data obtained with remdesivir resulted in its approval by the FDA on the 22 of October 2020 for COVID-19 treatment. At present, remdesivir is being recommended by several treatment guidelines for the treatment of COVID-19 patients. The evidence in favor of favipiravir is compromised by the small number and low-quality of trials conducted. Favipiravir has shown various benefits when administered in mild and moderate cases of COVID-19, while remdesivir was more beneficial in more severe cases of the disease. Since the two agents are suitable for different groups of patients, both drugs can play a significant role in fighting this pandemic. The goal of this work is to summarize the information available on two antimetabolites - remdesivir and favipiravir - and to compare clinical experience obtained so far with these two agents in COVID-19 patients.
Topics: Adenosine Monophosphate; Alanine; Amides; Humans; Pyrazines; RNA, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34782799
DOI: 10.5507/bp.2021.063 -
Chinese Medical Journal Jan 2022
Topics: AMP-Activated Protein Kinases; Adenosine Monophosphate; Kidney; Phosphorylation
PubMed: 34985025
DOI: 10.1097/CM9.0000000000001831 -
Revista Espanola de Quimioterapia :... Apr 2022
Topics: Adenosine Monophosphate; Alanine; Humans
PubMed: 35118854
DOI: 10.37201/req/147.2021