Darja Kanduc

Peptidology: short amino acid modules in cell biology and immunology

Summary.Short amino acid motifs, either linear sequences or discontinuous amino acid groupings, can interact with specific protein domains, so exerting a central role in cell adhesion, signal transduction, hormone activity, regulation of transcript expression, enzyme activity, and antigen-antibody interaction. Here, we analyze the literature for such critical short amino acid motifs to determine the minimal peptide length involved in biologically important interactions. We report the pentapeptide unit as a common minimal amino acid sequence critically involved in peptide-protein interaction and immune recognition. The present survey may have implications in defining the dimensional module for peptide-based therapeutical approaches such as the development of novel antibiotics, enzyme inhibitors/activators, mimetic agonists/antagonists of neuropeptides, thrombolitic agents, specific anti-viral agents, etc. In such a therapeutical context, it is of considerable interest that low molecular weight peptides can easily cross biological barriers, are less susceptible to protease attacks, and can be administered at high concentrations. In addition, small peptides are a rational target for strategies aimed at antigen-specific immunotherapeutical intervention. As an example, specific short peptide fragments might be used to elicit antibodies capable of reacting with the full-length proteins containing the peptide fragment’s amino acid sequence, so abolishing the risk of cross-reactivity.

Computer-assisted analysis of molecular mimicry between human papillomavirus 16 E7 oncoprotein and human protein sequences

The immunology of human papillomavirus (HPV) infections has peculiar characteristics. The long latency for cervical cancer development after primary viral infection suggests mechanisms that may aid the virus in avoiding the host immunosurveillance and establishing persistent infections. In order to understand whether molecular mimicry phenomena might explain the ability of HPV to avoid a protective immune response by the host cell, sequence similarity between HPV16 E7 oncoprotein and human self‐proteins was examined by computer‐assisted analysis. Data were obtained showing that the HPV16 E7 protein has high and widespread similarity to several human proteins involved in a number of critical regulatory processes. In addition, multiple identical and different E7 peptide motifs are present in the same human protein. Thus, sharing of common motifs between viral oncoproteins and molecules of normal cells may be one cause underlying the scarce immunogenicity of HPV infections. The hypothesis is advanced that synthetic peptides harbouring viral motifs not and/or scarcely represented in the hosts cellular proteins may represent a valuable immunotherapeutic approach for cervical cancer treatment.

Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond

Zika virus (ZIKV) infection during pregnancy may be linked to fetal neurological complications that include brain damage and microcephaly. How the viral infection relates to fetal brain malformations is unknown. This study analyzes ZIKV polyprotein for peptide sharing with human proteins that, when altered, associate with microcephaly and brain calcifications. Results highlight a vast viral versus human peptide commonality that, in particular, involves centriolar and centrosomal components canonically cataloged as microcephaly proteins, i.e., C2CD3, CASC5, CP131, GCP4, KIF2A, STIL, and TBG. Likewise, a search for ZIKV peptide occurrences in human proteins linked to Guillain-Barré-like syndromes also show a high, unexpected level of peptide sharing. Of note, further analyses using the Immune Epitope DataBase (IEDB) resource show that many of the shared peptides are endowed with immunological potential. The data indicate that immune reactions following ZIKV infection might be a considerable source of crossreactions with brain-specific proteins and might contribute to the ZIKV-associated neuropathologic sequelae.

Massive peptide sharing between viral and human proteomes

Abstract Thirty viral proteomes were examined for amino acid sequence similarity to the human proteome, and, in parallel, a control of 30 sets of human proteins was analyzed for internal human overlapping. We find that all of the analyzed 30 viral proteomes, independently of their structural or pathogenic characteristics, present a high number of pentapeptide overlaps to the human proteome. Among the examined viruses, human T-lymphotropic virus 1, Rubella virus, and hepatitis C virus present the highest number of viral overlaps to the human proteome. The widespread and ample distribution of viral amino acid sequences through the human proteome indicates that viral and human proteins are formed of common peptide backbone units and suggests a fluid compositional chimerism in phylogenetic entities canonically classified distantly as viruses and Homo sapiens. Importantly, the massive viral to human peptide overlapping calls into question the possibility of a direct causal association between virus–host sharing of amino acid sequences and incitement to autoimmune reactions through molecular recognition of common motifs.

Pre-eclampsia is associated with Helicobacter pylori seropositivity in Italy.

Objectives Pre-eclampsia (PE) is characterized by an excess of inflammation and endothelial dysfunction. Helicobacter pylori (H. pylori) causes chronic inflammatory changes and endothelial damage. We investigated the prevalence of seropositivity for IgG against H. pylori and cytotoxin-associated antigen A (CagA) in PE patients and the presence of H. pylori DNA in their placentas. Methods We tested 47 pregnant women with PE and 47 with uneventful pregnancies for serum antibodies against H. pylori (enzyme immunoassays) and CagA protein (immunoblot assays). In 20 of them (10 normal and 10 PE) we assessed the presence, in the placenta, of H. pylori DNA by means of nested polymerase chain reaction (PCR). The odds ratios (OR) and 95% confidence intervals (CI), adjusted for parity, were calculated using logistic regression analysis to assess the risk of PE associated with H. pylori infection. Results Helicobacter pylori seropositivity frequency was higher in mothers with PE (51.1%) compared to women with uneventful pregnancy (31.9%) (OR, 2.668; 95% CI, 1.084–6.566; P = 0.033). The difference was even greater for CagA seropositivity (80.9 and 14.9%, respectively) (OR, 26.035; 95% CI, 8.193–82.729; P < 0.001). All placentas were negative for H. pylori DNA. Conclusions Helicobacter pylori, and especially strains carrying the CagA gene, may contribute to the inflammatory mechanisms involved in the pathogenesis of PE.

DNA hypomethylation in ethionine-induced rat preneoplastic hepatocyte nodules

DNA from hepatocyte nodules induced in rats with dietary DL-ethionine and from the surrounding non-nodular liver contained less 5-methyldeoxycytidine per deoxycytidine when compared with that from normal adult liver. The degree of apparent hypomethylation, 37% in nodules and 20% in the surrounding liver, decreased somewhat (29% and 16% respectively) at 2 weeks after terminating the exposure to ethionine. Nodules and surrounding liver, like normal liver, responded to partial hepatectomy with a decrease in the 5-methyldeoxycytidine level at 24 hrs and a return to the level at the time of partial hepatectomy by 38 hrs. These findings indicate the need for careful control of cell proliferation in comparing the levels of a post-replicative DNA modification, methylation, in proliferating and non-proliferating cell populations. These findings also suggest that a portion of the hypomethylation in preneoplastic nodules may be due to a bona fide decrease in the level of cytosine methylation in the parental strand of DNA. This hypomethylation could be one basis for the altered gene expression in hepatocyte nodules, possible precursors for liver cancer.

Molecular mimicry of phage displayed peptides mimicking GD3 ganglioside

We have analyzed sequence homologies between nonimmunogenic phage displayed peptides mimicking GD3 ganglioside and human/mouse self-proteins. The GD3 ganglioside phagotopes showed homology to proteins involved in carbohydrate metabolism/transport. Besides this expected homology, molecular mimicry of critical regulatory proteins was found. These data contribute to our understanding of the structural relatedness of antigenic determinants defined by specific anti-GD3 monoclonal antibodies and, in addition, suggest that molecular mimicry might explain the nonimmunogenicity of these peptides otherwise characterized by specificity to the mAb counterpart. We conclude that construction of peptides harboring motifs absent or scarcely represented in endogenous self-proteins might be a useful approach in melanoma immunotherapy.

Cell Growth and Oncogenesis

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Non-self-discrimination as a driving concept in the identification of an immunodominant HMW-MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients

We analyzed the sera of patients with melanoma to define the human humoral autoantibody profile towards HMW‐MAA. Computational proteome scanning using the non‐self‐discrimination principle as a guide led to the individuation of the low‐similarity HMW‐MAA781–789RATVWMLRL peptide fragment as an immunodominant B‐cell epitope. Linear B‐cell determinant individuation was experimentally validated by dot blot immunoassay and NMR spectroscopy analysis. Regulation of physiologic self‐reactivity by the non‐self‐discrimination principle is discussed.

Epitopic peptides with low similarity to the host proteome: towards biological therapies without side effects

Background: A structured analysis of the literature indicates that a low level of sequence similarity to the host proteome modulates the B cell epitope pool in the humoral immune response toward protein antigens. From a clinical point of view, low-similarity peptides might have strong repercussions for the rational development of peptide-based treatments for cancer, autoimmunity and infectious diseases. The most attractive feature of the similarity concept is that it appears to guarantee the highest specificity and lowest cross-reactivity when designing effective, safe and theoretically infallible (immuno)therapeutic tools. Objective/methods: This review describes the research pathway from protein- to peptide-based therapies. Results/conclusions: Using the breast-cancer-associated BRCA2 protein as a model, the principle of sequence uniqueness is defined as the rationale for a pharmacological platform that might yield improved results in both patient survival and quality of life.