Mysticism and Philosophy

The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug de...

/pdf/the-protide-prodrug-technology-from-the-concept-to-the-58mrmlbgs4.pdf

The ProTide Prodrug Technology: From the Concept to the Clinic

SARS-CoV-2 is responsible for the current COVID-19 pandemic. On the basis of our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues (the triphosphates of Sofosbuvir, Alovudine, and AZT) inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). We also demonstrated that a library of additional nucleotide analogues terminate RNA synthesis catalyzed by the SARS-CoV-2 RdRp, a well-established drug target for COVID-19. Here, we used polymerase extension experiments to demonstrate that the active triphosphate form of Sofosbuvir (an FDA-approved hepatitis C drug) is incorporated by SARS-CoV-2 RdRp and blocks further incorporation. Using the molecular insight gained from the previous studies, we selected the active triphosphate forms of six other antiviral agents, Alovudine, Tenofovir alafenamide, AZT, Abacavir, Lamivudine, and Emtricitabine, for evaluation as inhibitors of the SARS-CoV-2 RdRp and demonstrated the ability of these viral polymerase inhibitors to be incorporated by SARS-CoV-2 RdRp, where they terminate further polymerase extension with varying efficiency. These results provide a molecular basis for inhibition of the SARS-CoV-2 RdRp by these nucleotide analogues. If sufficient efficacy of some of these FDA-approved drugs in inhibiting viral replication in cell culture is established, they may be explored as potential COVID-19 therapeutics.

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19.

While remdesivir has garnered much hope for its moderate anti-Covid-19 effects, its parent nucleoside, GS-441524, has been overlooked Pharmacokinetic analysis of remdesivir evidences premature serum hydrolysis to GS-441524; GS-441524 is the predominant metabolite reaching the lungs With its synthetic simplicity and in vivo efficacy in the veterinary setting, we contend that GS-441524 is superior to remdesivir for Covid-19 treatment

Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment

RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic.

The ProTide prodrug technology has proved very useful in the discovery of nucleotide therapeutics and has successfully led to two FDA-approved drugs. However, with the extensive application of this prodrug approach to nucleotides for nearly three decades, the intellectual property (IP) landscape is becoming congested and, to overcome this, new inventive applications of the ProTide prodrug technology are emerging.

The ProTide Prodrug Technology: Where Next?

Objective
Research into psychedelic therapy models has shown promise for the treatment of specific psychiatric conditions Mystical‐type experiences occasioned by psilocybin have been correlated with therapeutic benefits and long‐term improvements in positive mental outlook and attitudes This article aims to provide an overview of the topic, highlight strengths and weaknesses in current research, generate novel perspectives and discussion, and consider future avenues for research

Design
This narrative review was designed to summarise and assess the state of research on psilocybin occasioned mystical‐type experiences and applications for the treatment of specific psychiatric conditions

Results
Contemporary methods on the quantification of mystical‐type experiences and their acute subjective effects are discussed Recent studies provide some understanding of the pharmacological actions of psychedelics although the neurological similarities and differences between spontaneous and psychedelic mystical‐type experiences are not well described Applicability to modern clinical settings is assessed Potential novel therapeutic applications include use in positive psychology interventions in healthy individuals

Conclusions
Since 2006 significant advancements in understanding the therapeutic potential of psilocybin‐assisted psychotherapy have been made; however, more work is required to understand the neuromechanistic processes and applicability in modern clinical settings Despite promising results in recent studies, funding issues for clinical trials, legal concerns and socio‐cultural resistance provide a counterpoint to experimental evidence

Psilocybin occasioned mystical-type experiences.

Reports have indicated possible uses of ayahuasca for the treatment of conditions including depression, addictions, post‐traumatic stress disorder, anxiety and specific psychoneuroendocrine immune system pathologies. The article assesses potential ayahuasca and N,N‐dimethyltryptamine (DMT) integration with contemporary healthcare. The review also seeks to provide a summary of selected literature regarding the mechanisms of action of DMT and ayahuasca; and assess to what extent the state of research can explain reports of unusual phenomenology.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hup.2835

N,N‐dimethyltryptamine and Amazonian ayahuasca plant medicine

Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives.

BackgroundRecreational drug use is a major cause of disease, injury, physical and mental impairment and death in developed countries such as the United Kingdom and the United States. Alcohol, tobacco, cannabis, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybe mushrooms are recreational drugs with capacity to cause harm. Cannabis, MDMA and psilocybin have reported therapeutic applications.ObjectivesThe primary purpose of this study was to determine which of the three types of vendor (pharmacy, shop and the black market) are perceived to be the most suitable for selling the substances discussed according to a general population sample.MethodsA sample of 105 UK nationals was selected for the survey. Participants were presented information regarding reported relative dangers of alcohol, tobacco, cannabis, MDMA and psilocybin and potential therapeutic applications. Participants were then asked to review harm reduction strategies.ResultsIt was found that participants concluded that pharmacists with availa...

https://journals.sagepub.com/doi/pdf/10.1177/2050324518767441

Edward James

Papers

The ProTide Prodrug Technology: Where Next?

Psilocybin occasioned mystical-type experiences.

N,N‐dimethyltryptamine and Amazonian ayahuasca plant medicine

Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives.

Pharmacies as potential providers of harm reduction services: A preliminary online survey: