Evaluation of a hapten conjugate vaccine against the "zombie drug" xylazine.

Xylazine has emerged as a primary adulterant in fentanyl, exacerbating the complexity of the opioid crisis. Yet, there is no approved drug that can reverse xylazine's pathophysiology. As a prelude to monoclonal antibodies being assessed as a viable therapeutic, a vaccine inquiry was conducted evaluating the immune response in reversing xylazine induced behavior effects.

Development of a vaccine against the synthetic opioid U-47700.

Opioid use disorders and overdose have become a major public health concern in recent years. U-47700, a New psychoactive substances (NPS) opioid, also known as "pinky" or "pink" has been identified as a new threat in the drug supply because of its potency and abuse potential. Conjugate vaccines that can produce antibodies against target drug molecules have emerged as a promising tool to treat substance use disorders. Herein, we report the design, synthesis, and in vivo characterization of a U-47700 vaccine. The vaccine demonstrated favorable results with rodents producing elevated levels of antibody titer and sub-micromolar affinity to U-47700. In addition, antibodies generated by the vaccine effectively mitigated drug-induced effects by preventing the drug from penetrating the blood-brain barrier, which was verified by antinociception and drug biodistribution studies. The development of a vaccine against U-47700 and other NPS opioids contributes to the continued advancement of non-conventional pharmacological treatments to address the global opioid epidemic.

Catalytic Antibody Blunts Carfentanil-Induced Respiratory Depression.

Carfentanil, the most potent of the fentanyl analogues, is at the forefront of synthetic opioid-related deaths, second to fentanyl. Moreover, the administration of the opioid receptor antagonist naloxone has proven inadequate for an increasing number of opioid-related conditions, often requiring higher/additional doses to be effective, as such interest in alternative strategies to combat more potent synthetic opioids has intensified. Increasing drug metabolism would be one strategy to detoxify carfentanil; however, carfentanil's major metabolic pathways involve N-dealkylation or monohydroxylation, which do not lend themselves readily to exogenous enzyme addition. Herein, we report, to our knowledge, the first demonstration that carfentanil's methyl ester when hydrolyzed to its acid was found to be 40,000 times less potent than carfentanil in activating the µ-opioid receptor. Physiological consequences of carfentanil and its acid were also examined through plethysmography, and carfentanil's acid was found to be incapable of inducing respiratory depression. Based upon this information, a hapten was chemically synthesized and immunized, allowing the generation of antibodies that were screened for carfentanil ester hydrolysis. From the screening campaign, three antibodies were found to accelerate the hydrolysis of carfentanil's methyl ester. From this series of catalytic antibodies, the most active underwent extensive kinetic analysis, allowing us to postulate its mechanism of hydrolysis against this synthetic opioid. In the context of potential clinical applications, the antibody, when passively administered, was able to reduce respiratory depression induced by carfentanil. The data presented supports further development of antibody catalysis as a biologic strategy to complement carfentanil overdose reversal.

Demystifying the Druggability of the MYC Family of Oncogenes.

The MYC family of oncogenes (MYC, MYCN, and MYCL) encodes a basic helix-loop-helix leucine zipper (bHLHLZ) transcriptional regulator that is responsible for moving the cell through the restriction point. Through the HLHZIP domain, MYC heterodimerizes with the bHLHLZ protein MAX, which enables this MYC-MAX complex to bind to E-box regulatory DNA elements thereby controlling transcription of a large group of genes and their proteins. Translationally, MYC is one of the foremost oncogenic targets, and deregulation of expression of the MYC family gene/proteins occurs in over half of all human tumors and is recognized as a hallmark of cancer initiation and maintenance. Additionally, unexpected roles for this oncoprotein have been found in cancers that nominally have a non-MYC etiology. Although MYC is rarely mutated, its gain of function in cancer results from overexpression or from amplification. Moreover, MYC is a pleiotropic transcription factor possessing broad pathogenic prominence making it a coveted cancer target. A widely held notion within the biomedical research community is that the reliable modulation of MYC represents a tremendous therapeutic opportunity given its role in directly potentiating oncogenesis. However, the MYC-MAX heterodimer interaction contains a large surface area with a lack of well-defined binding sites creating the perception that targeting of MYC-MAX is forbidding. Here, we discuss the biochemistry behind MYC and MYC-MAX as it relates to cancer progression associated with these transcription factors. We also discuss the notion that MYC should no longer be regarded as undruggable, providing examples that a therapeutic window is achievable despite global MYC inhibition.

Mapping a Country Image from Global News Reports about COVID-19 Pandemic.

The outbreak of the coronavirus disease of 2019 (COVID-19) pandemic has infected hundreds of millions of people worldwide and caused millions of deaths. This study used media analysis and correlation analysis to elucidate the significant differences in the ways in which news reports from 228 countries discussed a specific country when covering the COVID-19 pandemic. Media reports analysed in this study were collected from the Global Database of Events, Language, and Tone project (GDELT). These differences were found to be deeply embedded in the economic, socio-political, and cultural contexts of different countries. The findings reinforced the hypothetical assumption in framing theory and promoted a measurable and upscaled use of framing theory into macro geography studies. This study highlights the urgent need of a geo-political examination of COVID-19 in the global context-an area with insufficient interest from interdisciplinary perspective beyond epidemiology. Further research can be of great value for the promotion of an effective international cooperation mechanism to curb the spread of COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s12061-022-09498-4.

Polyphosphazene: A New Adjuvant Platform for Cocaine Vaccine Development.

Cocaine is a highly addictive drug that has seen a steady uptrend causing severe health problems worldwide. Currently, there are no approved therapeutics for treating cocaine use disorder; hence, there is an urgent need to identify new medications. Immunopharmacotherapeutics is a promising approach utilizing endogenous antibodies generated through active vaccination, and if properly programmed, can blunt a drug's psychoactive and addictive effects. However, drug vaccine efficacy has largely been limited by the modest levels of antibodies induced. Herein, we explored an adjuvant system consisting of a polyphosphazene macromolecule, specifically poly[di(carboxylatoethylphenoxy)-phosphazene] (PCEP), a biocompatible synthetic polymer that was solicited for improved cocaine conjugate vaccine delivery performance. Our results demonstrated PCEP's superior assembling efficiency with a cocaine hapten as well as with the combined adjuvant CpG oligodeoxynucleotide (ODN). Importantly, this combination led to a higher titer response, balanced immunity, successful sequestering of cocaine in the blood, and a reduction in the drug in the brain. Moreover, a PCEP-cocaine conjugate vaccine was also found to function well via intranasal administration, where its efficacy was demonstrated through the antibody titer, affinity, mucosal IgA production, and a reduction in cocaine's locomotor activity. Overall, a comprehensive evaluation of PCEP integrated within a cocaine vaccine established an advance in the use of synthetic adjuvants in the drugs of abuse vaccine field.

Broadly Neutralizing Synthetic Cannabinoid Vaccines.

Synthetic cannabinoids (SCs) constitute a significant portion of psychoactive substances forming a major public health risk. Due to the wide variety of SCs, broadly neutralizing antibodies generated by active immunization present an intriguing pathway to combat cannabinoid use disorder. Here, we probed hapten design for antibody affinity and cross reactivity against two classes of SCs. Of the 10 haptens screened, 3 vaccine groups revealed submicromolar IC50, each targeting 5-6 compounds in our panel of 22 drugs. Moreover, SCs were successfully sequestered when administered by vaping or intraperitoneal injection, which was confirmed within animal models by observing locomotion, body temperature, and pharmacokinetics. We also discovered synergistic effects to simultaneously blunt two drug classes through an admixture vaccine approach. Collectively, our study provides a comprehensive foundation for the development of vaccines against SCs.

Pharmacokinetic Approach to Combat the Synthetic Cannabinoid PB-22.

Synthetic cannabinoids are part of a group of drugs called new psychoactive substances. Most of these cannabinoids are unregulated, and there are no therapeutic treatments for their addictive properties or reversing a potential overdose. Vaccination and catalytic antibodies strategies were investigated to assess their ability to blunt the psychoactive properties of the cannabinoid PB-22. To complement these antibody concentric investigations, we also disclose the discovery of the enzymatic degradation of this cannabinoid. Serum factors including albumin and carboxylesterase were found to catalyze the hydrolysis of PB-22. Affinity, kinetics, animal behavior, and biodistribution studies were utilized to evaluate the efficiency of these pharmacokinetic approaches. Our findings suggest simple antibody binding as the most efficacious means for altering PB-22's effect on the brain. Catalytic approaches only translated to esterases being capable of PB-22's degradation with a catalytic antibody approach providing no proclivity for PB-22's hydrolysis. Pharmacokinetic approaches provide a powerful strategy for treating substance abuse disorders and overdose for drugs where no therapeutic is available.

Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice.

Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.

Supramolecular "Trojan Horse" for Nuclear Delivery of Dual Anticancer Drugs.

Nuclear delivery and accumulation are very important for many anticancer drugs that interact with DNA or its associated enzymes in the nucleus. However, it is very difficult for neutrally and negatively charged anticancer drugs such as 10-hydroxycamptothecine (HCPT). Here we report a simple strategy to construct supramolecular nanomedicines for nuclear delivery of dual synergistic anticancer drugs. Our strategy utilizes the coassembly of a negatively charged HCPT-peptide amphiphile and the positively charged cisplatin. The resulting nanomaterials behave as the "Trojan Horse" that transported soldiers (anticancer drugs) across the walls of the castle (cell and nucleus membranes). Therefore, they show improved inhibition capacity to cancer cells including the drug resistant cancer cell and promote the synergistic tumor suppression property in vivo. We envision that our strategy of constructing nanomaterials by metal chelation would offer new opportunities to develop nanomedicines for combination chemotherapy.