Heat Shock Proteins: A Dual Carrier-adjuvant for an Anti-drug Vaccine Against Heroin

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2018 Dec 1

PMID 30497790

Citations 8

Authors

Candy S Hwang

Beverly Ellis

Bin Zhou

Kim D Janda

Affiliations

Soon will be listed here.

Abstract

Heroin is a highly abused opioid that has reached epidemic status within the United States. Yet, existing therapies to treat addiction are inadequate and frequently result into rates of high recidivism. Vaccination against heroin offers a promising alternative therapeutic option but requires further development to enhance the vaccine's performance. Hsp70 is a conserved protein with known immunomodulatory properties and is considered an excellent immunodominant antigen. Within an antidrug vaccine context, we envisioned Hsp70 as a potential dual carrier-adjuvant, wherein immunogenicity would be increased by co-localization of adjuvant and antigenic drug hapten. Recombinant Mycobacterium tuberculosis Hsp70 was appended with heroin haptens and the resulting immunoconjugate granted anti-heroin antibody production and blunted heroin-induced antinociception. Moreover, Hsp70 as a carrier protein surpassed our benchmark Her-KLH cocktail through antibody-mediated blockade of 6-acetylmorphine, the main mediator of heroin's psychoactivity. The work presents a new avenue for exploration in the use of hapten-Hsp70 conjugates to elicit anti-drug immune responses.

Citing Articles

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References

Bremer P, Schlosburg J, Banks M, Steele F, Zhou B, Poklis J . Development of a Clinically Viable Heroin Vaccine. J Am Chem Soc. 2017; 139(25):8601-8611. PMC: 5612493. DOI: 10.1021/jacs.7b03334. View

Bendz H, Ruhland S, Pandya M, Hainzl O, Riegelsberger S, Brauchle C . Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling. J Biol Chem. 2007; 282(43):31688-702. DOI: 10.1074/jbc.M704129200. View

Lockner J, Eubanks L, Choi J, Lively J, Schlosburg J, Collins K . Flagellin as carrier and adjuvant in cocaine vaccine development. Mol Pharm. 2014; 12(2):653-62. PMC: 4319694. DOI: 10.1021/mp500520r. View

Stowe G, Vendruscolo L, Edwards S, Schlosburg J, Misra K, Schulteis G . A vaccine strategy that induces protective immunity against heroin. J Med Chem. 2011; 54(14):5195-204. PMC: 3142939. DOI: 10.1021/jm200461m. View

Schlosburg J, Vendruscolo L, Bremer P, Lockner J, Wade C, Nunes A . Dynamic vaccine blocks relapse to compulsive intake of heroin. Proc Natl Acad Sci U S A. 2013; 110(22):9036-41. PMC: 3670323. DOI: 10.1073/pnas.1219159110. View

Shima F, Uto T, Akagi T, Akashi M . Synergistic stimulation of antigen presenting cells via TLR by combining CpG ODN and poly(γ-glutamic acid)-based nanoparticles as vaccine adjuvants. Bioconjug Chem. 2013; 24(6):926-33. DOI: 10.1021/bc300611b. View

Kosten T, Domingo C, Shorter D, Orson F, Green C, Somoza E . Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. Drug Alcohol Depend. 2014; 140:42-7. PMC: 4073297. DOI: 10.1016/j.drugalcdep.2014.04.003. View

Sulima A, Jalah R, Antoline J, Torres O, Imler G, Deschamps J . A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross-React Immunologically with Related Drugs of Abuse. J Med Chem. 2017; 61(1):329-343. PMC: 5767880. DOI: 10.1021/acs.jmedchem.7b01427. View

Ohia-Nwoko O, Kosten T, Haile C . Animal Models and the Development of Vaccines to Treat Substance Use Disorders. Int Rev Neurobiol. 2016; 126:263-91. DOI: 10.1016/bs.irn.2016.02.009. View

10.

Binder R . Heat-shock protein-based vaccines for cancer and infectious disease. Expert Rev Vaccines. 2008; 7(3):383-93. DOI: 10.1586/14760584.7.3.383. View

11.

Tobian A, Canaday D, Harding C . Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells. J Immunol. 2004; 173(8):5130-7. DOI: 10.4049/jimmunol.173.8.5130. View

12.

Kimishima A, Wenthur C, Zhou B, Janda K . An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life. ACS Chem Biol. 2017; 12(1):36-40. PMC: 6434689. DOI: 10.1021/acschembio.6b00977. View

13.

van Wijk F, Prakken B . Heat shock proteins: Darwinistic immune modulation on dangerous grounds. J Leukoc Biol. 2010; 88(3):431-4. DOI: 10.1189/jlb.0410236. View

14.

Pollini R, Banta-Green C, Cuevas-Mota J, Metzner M, Teshale E, Garfein R . Problematic use of prescription-type opioids prior to heroin use among young heroin injectors. Subst Abuse Rehabil. 2013; 2(1):173-180. PMC: 3536052. DOI: 10.2147/SAR.S24800. View

15.

Takemoto S, Nishikawa M, Guan X, Ohno Y, Yata T, Takakura Y . Enhanced generation of cytotoxic T lymphocytes by heat shock protein 70 fusion proteins harboring both CD8(+) T cell and CD4(+) T cell epitopes. Mol Pharm. 2010; 7(5):1715-23. DOI: 10.1021/mp1001069. View

16.

Ko S, Kim J, Na D, Park S, Park S, Hyun J . A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities. Chem Biol. 2015; 22(3):391-403. DOI: 10.1016/j.chembiol.2015.02.004. View

17.

Motta A, Schmitz C, Rodrigues L, Ribeiro F, Teixeira C, Detanico T . Mycobacterium tuberculosis heat-shock protein 70 impairs maturation of dendritic cells from bone marrow precursors, induces interleukin-10 production and inhibits T-cell proliferation in vitro. Immunology. 2007; 121(4):462-72. PMC: 2265970. DOI: 10.1111/j.1365-2567.2007.02564.x. View

18.

Lopez-Buesa P, Pfund C, Craig E . The biochemical properties of the ATPase activity of a 70-kDa heat shock protein (Hsp70) are governed by the C-terminal domains. Proc Natl Acad Sci U S A. 1998; 95(26):15253-8. PMC: 28029. DOI: 10.1073/pnas.95.26.15253. View

19.

Barrios C, Georgopoulos C, Lambert P, Del Giudice G . Heat shock proteins as carrier molecules: in vivo helper effect mediated by Escherichia coli GroEL and DnaK proteins requires cross-linking with antigen. Clin Exp Immunol. 1994; 98(2):229-33. PMC: 1534419. DOI: 10.1111/j.1365-2249.1994.tb06130.x. View

20.

Karinen R, Andersen J, Ripel A, Hasvold I, Hopen A, Morland J . Determination of heroin and its main metabolites in small sample volumes of whole blood and brain tissue by reversed-phase liquid chromatography-tandem mass spectrometry. J Anal Toxicol. 2009; 33(7):345-50. DOI: 10.1093/jat/33.7.345. View