Drugs as Haptens, Antigens, and Immunogens

Park, B. Kevin; Sanderson, Joseph P.; Naisbitt, Dean J.

doi:10.1159/000104189

Cited by 12 publications

(14 citation statements)

References 54 publications

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“…Protein covalent binding emerged as a mechanism of drug toxicity in the early 1970s and many marketed drugs that have been associated with idiosyncratic adverse drug reactions (ADRs) are known to form reactive metabolites that are capable of covalently modifying proteins [52–54]. Immune-mediated ADRs are thought to be caused by an abnormal immune reaction triggered by an immunogenic drug–protein adduct [46–48]. According to the hapten hypothesis, drugs are too small to stimulate an immune response; however, the drug or metabolite can act as a hapten upon covalent binding to a protein.…”

Section: Potential Disadvantages Of Covalent Inhibitorsmentioning

confidence: 99%

Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors

Johnson

Weerapana

Cravatt³

2010

Future Med. Chem.

342

307

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This article presents several covalent inhibitors, including examples of successful drugs, as well as highly selective, irreversible inhibitors of emerging therapeutic targets, such as fatty acid amide hydolase. Covalent inhibitors have many desirable features, including increased biochemical efficiency of target disruption, less sensitivity toward pharmacokinetic parameters and increased duration of action that outlasts the pharmacokinetics of the compound. Safety concerns that must be mitigated include lack of specificity and the potential immunogenicity of protein-inhibitor adduct(s). Particular attention will be given to recent technologies, such as activity-based protein profiling, which allow one to define the proteome-wide selectivity patterns for covalent inhibitors in vitro and in vivo. For instance, any covalent inhibitor can, in principle, be modified with a 'clickable' tag to generate an activity probe that is almost indistinguishable from the original agent. These probes can be applied to any living system across a broad dose range to fully inventory their on and off targets. The substantial number of drugs on the market today that act by a covalent mechanism belies historical prejudices against the development of irreversibly acting therapeutic small molecules. Emerging proteomic technologies offer a means to systematically discriminate safe (selective) versus deleterious (nonselective) covalent inhibitors and thus should inspire their future design and development. Brief history & examples of covalent inhibitorsThe design of selective covalent inhibitors is conceptually very attractive but in practice hard to achieve. That is because it is difficult to strike the right balance between reactivity and selectivity. In many cases, a highly electrophilic species (e.g., α-halo ketone, α,β-unsaturated ketone, fluorophosphonate (FP) or cyanamide) needs to be incorporated into the inhibitor to achieve covalent modification of a protein target [1]. Alkylation of other macromolecules can take place in vivo, leading to deleterious effects, or the reactive species may be scavenged by ubiquitous low-molecular-weight nucleophiles such as glutathione. †

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Section: Potential Disadvantages Of Covalent Inhibitorsmentioning

confidence: 99%

Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors

Johnson

Weerapana

Cravatt³

2010

Future Med. Chem.

342

307

View full text Add to dashboard Cite

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“…Antigen-presenting cells involved in CADR have not been clearly identified. In vitro, blood-derived dendritic-like cells from sensitized patients present drug-protein complexes to T cells (Poszeczynska-Guigné et al, 2005;Rodriguez-Pena et al, 2006;Park et al, 2007;Sanderson et al, 2007). Moreover, mononuclear-derived DC (Mo-DC) were shown to upregulate expression of maturation and activation markers (CD40, CD86 and HLA-DR) on exposure to sulfamethoxazole or amoxicillin , although for the latter preferentially on cells from patients with previous amoxicillin induced- MPE (Rodriguez-Pena et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Systemic drugs inducing non‐immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP‐1 cells

Gonçalo

Martins

Silva

et al. 2014

J of Applied Toxicology

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Contact sensitizers induce phenotypic and functional changes in dendritic cells (DC) that enhance their antigen-presenting capacity and, ultimately, modulate the T cell response. To evaluate if there is a similar effect of drugs causing T-cell-mediated cutaneous adverse drug reactions (CADR), we studied the in vitro effect of drugs on THP-1 cells, a cell line widely used to evaluate the early molecular and cellular events triggered by contact sensitizers. The effect of allopurinol, oxypurinol, ampicillin, amoxicillin, carbamazepine and sodium valproate, at EC30 concentrations, was evaluated on p38 MAPK activation, by Western Blot, and on the expression of genes coding for DC maturation markers, pro-inflammatory cytokine/chemokines and hemeoxygenase 1 (HMOX1), by real-time RT-PCR. Results were compared with lipopolysaccharide (LPS), a DC maturation stimulus, and the strong contact sensitizer, 1-fluoro-2,4-dinitrobenzene (DNFB). All drugs studied significantly upregulated HMOX1 gene transcription and all, except the anticonvulsants, also upregulated IL8. Allopurinol and oxypurinol showed the most intense effect, in a magnitude similar to DNFB and superior to betalactams. Transcription of CD40, IL12B and CXCL10 genes by drugs was more irregular. Moreover, like DNFB, all drugs activated p38 MAPK, although significantly only for oxypurinol. Like contact sensitizers, drugs that cause non-immediate CADR activate THP-1 cells in vitro, using different signalling pathways and affecting gene transcription with an intensity that may reflect the frequency and severity of the CADR they cause. Direct activation of antigen-presenting DC by systemic drugs may be an important early step in the pathophysiology of non-immediate CADR.

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“…In case of penicillins, stable protein conjugates formed include penicilloyl (major) determinants and other minor determinants. 13 For cephalosporin, however, haptenic determinants are less clear. 14 Once inside the body, cephalosporins undergo rapid fragmentation of the BL nucleus and dihydrothiazine rings.…”

Section: Mechanism Of Beta-lactam Hypersensitivitymentioning

confidence: 99%

Use of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited

Qu¹

2014

Hong Kong Med J

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A 10% cross-reactivity rate is commonly cited between penicillins and cephalosporins. However, this figure originated from studies in the 1960s and 1970s which included first-generation cephalosporins with similar side-chains to penicillins. Cephalosporins were frequently contaminated by trace amount of penicillins at that time. The sidechain hypothesis for beta-lactam hypersensitivity is supported by abundant scientific evidence. Newer generations of cephalosporins possess side-chains that are dissimilar to those of penicillins, leading to low cross-reactivity. In the assessment of crossreactivity between penicillins and cephalosporins, one has to take into account the background betalactam hypersensitivity, which occurs in up to 10% of patients. Cross-reactivity based on skin testing or in-vitro test occurs in up to 50% and 69% of cases, respectively. Clinical reactivity and drug challenge test suggest an average cross-reactivity rate of only 4.3%. For third-and fourth-generation cephalosporins, the rate is probably less than 1%. Recent international guidelines are in keeping withUse of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited The ten per cent myth about betalactam cross-reactivityPenicillins and cephalosporins are two groups of widely prescribed antibiotics. They belong to the class of beta-lactam (BL) antibiotics because both possess the same BL nucleus. Allergic reactions are common side-effects of BL antibiotics. Studies in the 1960s and 1970s frequently estimated 10% crossreactivity between penicillins and cephalosporins. 1,2 However, at least two recent reviews showed much lower cross-reactivity. 3,4 Notably, cross-reactivity is higher between penicillins and first-and secondgeneration cephalosporins compared with thirdand fourth-generation cephalosporins. 5 The latter two groups are considered safe alternatives for patients with penicillin hypersensitivity. 6 The 10% cross-reactivity rate has recently been questioned as a medical myth. 4,7 Yet until 2005, an influential drug reference such as the British National Formulary (BNF) abided by the "10% rule". 8 Faced with such recommendation, an ordinary physician naturally avoids all BL antibiotics in patients with a history

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Drugs as Haptens, Antigens, and Immunogens

Cited by 12 publications

References 54 publications

Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors

Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors

Systemic drugs inducing non‐immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP‐1 cells

Use of cephalosporins in patients with immediate penicillin hypersensitivity: cross-reactivity revisited

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