ProteoIQ Quant

Humanized monoclonal antibodies targeting hypoxic human tumors via two distinct extracellular domains of carbonic anhydrase IX.

Hypoxia of the tumor microenvironment (TME) is often the main factor in the development of cancer. Also, low oxygen levels in tumor tissues may indicate that first or second line treatment will not be successful. This knowledge leads to the inevitable search for different types of therapy that successfully treat aggressive tumors. Due to its exclusive expression on tumor cells, carbonic anhydrase IX belongs to the group of most specific targets in hypoxic tumors. CA IX possesses several unique qualities that predetermine its pivotal role in targeted therapy. Its expression in the cell membrane makes it an easily accessible target, while its absence in the corresponding healthy tissue makes the treatment practically innocuous. The presence of CA IX in solid tumors results in an acidic environment that can lead to failure of standard therapy.
Hybridomas were humanized in parental mice (IV/18 and VII/20) for antibodies subsequently designated CA9hu-1 and CA9hu-2. From each hybridoma we obtained 25 copies. Each clone was analyzed for antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity, affinity, extracellular pH measurement, multicellular assembly analysis, and real-time monitoring of invasion using the xCELLigence system.
Based on the results of in vivo experiments, we selected mouse monoclonal antibodies VII/20 and IV/18. The former targets the conformational epitope of the stimulatory domain, is internalized after binding to antigen, and stops tumor growth while preventing extracellular acidification. . The second targets the sequential epitope of the protease-glucan domain, is not internalized, and is capable of blocking the attachment of tumor cells to the matrix to prevent the formation of metastases. In vitro experiments demonstrated that the humanized versions of the parental mouse antibodies, CA9hu-1 and CA9hu-2, retained these properties. They can reverse the failure of standard treatment as a result of an acidic environment by modulating TMEs, which are capable of inducing an immune response and have a high affinity, in addition to the activity of ADCC and CDC.
CA9hu-1 and CA9hu-2 are the first humanized antibodies against CA IX that have the potential to become suitable therapies for hypoxic tumors. These antibodies can be used to treat primary tumors and suppress metastasis.

Opportunities to target drugs on their way to nanoclusters in Ras

Disruption of native membrane regulation of Ras by the farnesyltransferase inhibitor tipifarnib in the late 1990s constituted the first indirect approach to drug targeting Ras. Since then, our understanding of how Ras dynamically migrates between subcellular sites has changed dramatically. Ras proteins must reach the plasma membrane to efficiently propagate the MAPK signal. At the plasma membrane, Ras proteins are organized into clusters of isoform-specific lipoproteins called nanoclusters. Recent evidence indicates that the main nanocluster has a specific lipid composition, supporting the recruitment of effectors such as Raf. In contrast, effectors possess lipid recognition motifs, which appear to act as lipid domain ubiquitination reagents for a specific Ras isoform. Evidence indicates that dimeric Raf proteins then assemble dimeric Ras into a non-mobile complex, thus forming the minimal unit of the active nanocluster. Here we review the novel and well-established trafficking chaperones and trafficking factors of Ras, along with the variety of lipid and protein adapters in the Ras nanocluster. We highlight approaches and opportunities targeting drugs against these determinants for regulation of functional Ras membrane. Finally, we consider the implications of Ras signaling in polarized cells, such as the epithelium, which is a common origin of tumorigenesis.

Proteome transcriptome integrative signatures and immunohistochemical modeling of the HIV-1 elite checkpoint phenotype: a debate between glycolysis and HIF signaling.

Natural control of HIV-1 is characteristic of less than 1% of individuals infected with HIV-1, the so-called elite controllers (EC). In this study, we sought to identify the signaling pathways associated with the CD phenotype using integrative transcriptome analysis and immunophenotyping. We found HIF signaling and glycolysis as specific features of the EC phenotype along with dysregulation of the

Analytical modulation and altered HIF signaling is a unique feature of the male CD phenotype that may contribute to normal control of HIV-1.

Biochemical characterization of the interaction between KRAS and Argonaute 2 .

Oncogenic mutations in KRAS lead to a constitutively active GTP-binding form that, in turn, activates several proliferative pathways. However, due to its compact and simple structure, targeting KRAS directly with small molecule drugs is challenging. Another approach is to identify target proteins that interact with KRAS. Argonaute 2 (AGO2) was recently identified as a protein that facilitates RAS-driven tumorigenesis. While previous studies described the in vivo effect of AGO2 on cancer progression in cells harboring mutant KRAS, here we sought to examine their direct interaction using purified proteins. We show that full-length AGO2 co-immunoprecipitated with KRAS using purified components; however, a complex between FL AGO2 and KRAS could not be isolated. We also generated a smaller N-terminal portion of AGO2 (NtAGO2) that is believed to be the major KRAS binding site. The complex with NtAGO2 can be detected by ion mobility mass spectrometry and size exclusion chromatography. However, the data indicate that the interaction of KRAS with purified AGO2 (NtAGO2 or FL AGO2) is weak and likely requires additional cellular components or protein forms of AGO2 that are not readily available in our purified assay systems. Future studies are needed to determine the conformation or modifications required by AGO2 to enrich the association with KRAS and regulate its activities.

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Harmonic analysis of fluoro, chloro and proteoalkene isostearates Gly Pro and Pro-Pro for collagen mimetics.

Collagen is the most abundant human protein, with the canonical sequence (Gly-Pro-Hyp)n in the triple helix region. Cis-trans isomerization of the amide Xaa-Pro made two of these amide bonds a target for alkene substitution: the Gly-Pro and Pro-Hyp positions. The coincidence of the Gly-Pro and Pro-Pro models (like the Pro-Hyp model) was computationally verified by simulations of fluoro-chloro- and proteoalkenes to determine whether these alkenes could stabilize collagen polyproline type II (PPII) formation. . Second-order Møller-Plesset (MP2) calculations with different base groups were used to perform agreement analyzes and locate fixed points. The results of the calculations predict that the fluoro and chloroalkene mimetics of Gly-Pro and Pro-Pro could participate in the n → π* donation to stabilize the PPII conformation, but are poor acceptors of n → π*, shifting the lower bounds. . globally away from the PPII conformer. For proteoalkyne mimics, the lack of significant n → π* interactions and the unstable geometry of PPII-likes explain their known triple-helix instability in collagen-like peptides.

Stress reduction of sulfur-containing amino acids in proteins and the implications of protein-lipid tandem damage

Radical stress reduction represents the other side of the redox spectrum, less studied but equally important compared to oxidative stress. The interaction of hydrogen atoms (H•) and hydrated electrons (e-aq) bound to peptides/proteins, focusing on the chemical transformations of methionine (Met) and cysteine ​​(CysS-SCys) residues into α-acid aminobutyric and alanine, respectively, has been summarized. The chemical and mechanical aspects of the desulfurization processes with the formation of diffusible radicals concentrated in sulfur, such as the metanetyl (CH3S•) and sulfhydryl (HS•) radicals, are analyzed. These results also apply to biomimetic radical chemistry, modeling the occurrence of tandem protein and lipid damage in lipoproteins and demonstrating that the generation of sulfur-focused radicals from a variety of proteins is coupled to the cis patterns of the lipids. unsaturated in the membranes. . Recent applications from pharmaceutical and pharmacological contexts have been described, illustrating new perspectives on formulation stability and drug mode of action, respectively.

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