Publications by authors named "Tyson Belz"

9 Publications

  • Page 1 of 1

Evaluation of a Series of Lipidated Tucaresol Adjuvants in a Hepatitis C Virus Vaccine Model.

ACS Med Chem Lett 2020 Dec 29;11(12):2428-2432. Epub 2020 Oct 29.

Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

Hepatitis C virus (HCV) infections represent a global health challenge; however, developing a vaccine for treatment of HCV infection has remained difficult as heterogeneous HCV contains distinct genotypes, and each genotype contains various subtypes and different envelope glycoproteins. Currently, there is no effective preventive vaccine for achieving global control over HCV. In our efforts to improve upon current HCV vaccines we designed a synthetically accessible adjuvant platform, wherein we synthesized 11 novel lipidated tucaresol analogues to assess their immunological potential. Using a tucaresol-based adjuvant approach, truncated lipid-variants together with an engineered E1E2 antigen construct, namely E2ΔTM3, elicited antibody (Ab) responses that were significantly higher than tucaresol. In sum, antibody end-point titer values largely corroborated HCV neutralization data with a simplified lipidated tucaresol variant affording the highest end point titer and % neutralization. This study lays the groundwork for additional permutations in tucaresol adjuvant design, including the examination of other proteins in vaccine development.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734796PMC
December 2020

Anti-Opioid Antibodies in Individuals Using Chronic Opioid Therapy for Lower Back Pain.

ACS Pharmacol Transl Sci 2020 Oct 25;3(5):896-906. Epub 2020 Aug 25.

School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States.

In addition to the risk of developing opioid use disorder (OUD), known side-effects of long-term opioid use include chronic inflammation and hyperalgesia, which may arise from immune responses induced following chronic opioid use. To investigate this hypothesis, blood samples were obtained from individuals with chronic back pain who were either chronically taking prescription opioids or had minimal recent opioid exposure. Patient samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) against hydrocodone- or oxycodone-hapten conjugates to assess the levels of antibodies present in the samples. While no specific response was seen in opioid-naïve subjects, we observed varying levels of anti-opioid IgM antibodies in the exposed subjects. In these subjects, antibody formation was found to be weakly correlated with current reported daily opioid dose. Other drugs of abuse found to elicit an immune response have been shown to generate advanced glycation end-products (AGEs) through reaction with glucose and subsequent modification of self-proteins. Investigations into this potential mechanism of anti-opioid antibody production identified reduced the formation of reactive intermediate species upon norhydrocodone reaction with glucose in comparison with nornicotine, thus identifying potentially important differences in hapten processing to yield the observed adaptive immune response.
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http://dx.doi.org/10.1021/acsptsci.0c00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551707PMC
October 2020

Sulfonate-isosteric replacement examined within heroin-hapten vaccine design.

Bioorg Med Chem Lett 2020 09 4;30(17):127388. Epub 2020 Jul 4.

Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States. Electronic address:

Heroin overdose and addiction remain significant health and economic burdens in the world today costing billions of dollars annually. Moreover, only limited pharmacotherapeutic options are available for treatment of heroin addiction. In our efforts to combat the public health threat posed by heroin addiction, we have developed vaccines against heroin. To expand upon our existing heroin-vaccine arsenal, we synthesized new aryl and alkyl sulfonate ester haptens; namely aryl-mono-sulfonate (H) and Aryl/alkyl-di-sulfonate (H) as carboxyl-isosteres of heroin then compared them to our model heroin-hapten (H) through vaccination studies. Heroin haptens were conjugated to the carrier protein CRM and the resulting CRM-immunoconjugates were used to vaccinate Swiss Webster mice following an established immunization protocol. Binding studies revealed that the highest affinity anti-heroin antibodies were generated by the H vaccine followed by the H and H vaccines, respectively (H > H≫H). However, neither the H nor H vaccines were able to generate high affinity antibodies to the psychoactive metabolite 6-acetyl morphine (6-AM), in comparison to the H vaccine. Blood brain bio-distribution studies supported these binding results with vaccine efficiency following the trend H > H ≫ H The work described herein provides insight into the use of hapten-isosteric replacement in vaccine drug design.
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http://dx.doi.org/10.1016/j.bmcl.2020.127388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398700PMC
September 2020

Enhancement of a Heroin Vaccine through Hapten Deuteration.

J Am Chem Soc 2020 08 27;142(31):13294-13298. Epub 2020 Jul 27.

Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

The United States is in the midst of an unprecedented epidemic of opioid substance use disorder, and while pharmacotherapies including opioid agonists and antagonists have shown success, they can be inadequate and frequently result in high recidivism. With these challenges facing opioid use disorder treatments immunopharmacotherapy is being explored as an alternative therapy option and is based upon antibody-opioid sequestering to block brain entry. Development of a heroin vaccine has become a major research focal point; however, producing an efficient vaccine against heroin has been particularly challenging because of the need to generate not only a potent immune response but one against heroin and its multiple psychoactive molecules. In this study, we explored the consequence of regioselective deuteration of a heroin hapten and its impact upon the immune response against heroin and its psychoactive metabolites. Deuterium (H) and cognate protium heroin (H) haptens were compared head to head in an inclusive vaccine study. Strikingly the H vaccine granted greater efficacy in blunting heroin analgesia in murine behavioral models compared to the H vaccine. Binding studies confirmed that the H vaccine elicited both greater quantities and equivalent or higher affinity antibodies toward heroin and 6-AM. Blood-brain biodistribution experiments corroborated these affinity tests. These findings suggest that regioselective hapten deuteration could be useful for the resurrection of previous drug of abuse vaccines that have met limited success in the past.
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http://dx.doi.org/10.1021/jacs.0c05219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544008PMC
August 2020

An atypical interaction explains the high-affinity of a non-hydrolyzable S-linked 1,6-α-mannanase inhibitor.

Chem Commun (Camb) 2017 Aug 2;53(66):9238-9241. Epub 2017 Aug 2.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.

The non-hydrolyzable S-linked azasugars, 1,6-α-mannosylthio- and 1,6-α-mannobiosylthioisofagomine, were synthesized and shown to bind with high affinity to a family 76 endo-1,6-α-mannanase from Bacillus circulans. X-ray crystallography showed an atypical interaction of the isofagomine nitrogen with the catalytic acid/base. Molecular dynamics simulations reveal that the atypical binding results from sulfur perturbing the most stable form away from the nucleophile interaction preferred for the O-linked congener.
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http://dx.doi.org/10.1039/c7cc04977cDOI Listing
August 2017

A building block approach to the synthesis of a family of S-linked α-1,6-oligomannosides.

Carbohydr Res 2016 Jun 13;429:38-47. Epub 2016 Apr 13.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address:

The syntheses of α-1,6-S-linked methyl di-, tetra- and hexamannosides are reported. The sulfur linkages are generated through coupling of thiolates (derived from anomeric thioacetates or isothiouronium bromides) with 6-deoxy-6-iodo sugars. Two approaches are detailed that involve [2 + 2 + 2] construction from either the reducing end or the non-reducing end. In constructing from the reducing end, coupling of a disaccharide thioacetate with a 6'-iodo reducing end disaccharide, followed by activation of the resulting tetrasaccharide to a 6'''-iodide, and iterative coupling with the same disaccharide thioacetate afforded the S-linked hexasaccharide, as well as the intermediate di- and tetrasaccharides. On the other hand, construction from the non-reducing end involved coupling of the above disaccharide thioacetate with an anomeric S-trityl protected 6'-iodo disaccharide. The resulting S-trityl tetrasaccharide was converted to a tetrasaccharide thioacetate, which was coupled with the same anomeric S-trityl protected 6'-iodo disaccharide to afford the hexasaccharide, which was elaborated to the methyl thioglycoside. The developed methodology may prove useful for the construction of other S-linked oligosaccharides.
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http://dx.doi.org/10.1016/j.carres.2016.04.015DOI Listing
June 2016

Evidence for a boat conformation at the transition state of GH76 α-1,6-mannanases--key enzymes in bacterial and fungal mannoprotein metabolism.

Angew Chem Int Ed Engl 2015 Apr 13;54(18):5378-82. Epub 2015 Mar 13.

Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK).

α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an (O) S2 conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through (O) S2 and B2,5 (≠) conformations, information that should inspire the development of new antifungal agents.
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http://dx.doi.org/10.1002/anie.201410502DOI Listing
April 2015

Synthesis Characterization and Antibacterial, Antifungal Activity of N-(Benzyl Carbamoyl or Carbamothioyl)-2-hydroxy Substituted Benzamide and 2-Benzyl Amino-Substituted Benzoxazines.

Int J Med Chem 2013 31;2013:436397. Epub 2013 Oct 31.

School of Pharmacy and Applied Science, La Trobe University, P.O. Box 199, Bendigo, UIC 3552, Australia.

New N-(benzyl carbamothioyl)-2-hydroxy substituted benzamides 13, 20, and 21 were synthesized using sodium bicarbonate and benzyl amine with 2-thioxo-substituted-1,3-benzoxazines 6, 10a, b, 11c, and 12a-n. The 2-thioxo-substituted-1,3-oxazines 6, 10a-b, 11d 12a-n, and 26 were converted to the corresponding 2-methylthio-substituted-1,3-oxazines 14a-l and 24 which were then converted to 2-benzyl amino-substituted-benzoxazines 15a-i by refluxing with benzylamine. Products 15a, b, e, f, and g were also synthesized by boiling the corresponding N-(benzyl carbamothioyl)-2-hydroxy substituted benzamides 13a, b, f, l, and m in acetic acid. 2-Oxo-substituted-1,3-benzoxazines 22 and 25 were prepared by treating the corresponding 2-methylthio-substituted-1,3-oxazines 14 and 24 with dilute HCl. The N-(benzyl carbamoyl)-2-hydroxy substituted benzamide 23 was synthesized from the reaction of 2-oxo-substituted-1,3-benzoxazine 22 with benzylamine. The new products were characterized using IR, (1)H, and (13)C NMR in addition to microanalysis. Selected compounds were tested in vitro for antibacterial and antifungi activity and the most active compounds were found to be the 4-(substituted-benzylamino)-2-hydroxy benzoic acids 9a and d (M. chlorophenolicum, MIC 50 and 25 µgm L(-1), resp.), N1, N3-bis (benzyl carbamothioyl)-4,6-dihydroxy-substituted phthalamides 20a and 20c (B. subtilis MIC 12.5, 50 µgm L(-1), resp.) and 21 (M. chlorophenolicum, MIC 50 µgm L(-1)).
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http://dx.doi.org/10.1155/2013/436397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207449PMC
November 2014
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