Biology subjects

Jordaan, G.

Publications and source records attributed to Jordaan, G..

4 recordsLinked to original sources

bioRxiv2026

Prefusion-specific glycoprotein B human antibodies protect against neonatal HSV-2 infection

Herpes simplex virus (HSV) causes severe neonatal infections and long-term neurological issues, with antivirals offering limited efficacy and no approved vaccines. Viral entry requires glycoprotein B (gB) for membrane fusion, yet no human antibodies to the prefusion form of gB have been identified, and antibodies targeting vulnerable epitopes are limited. We used prefusion-stabilized HSV-2 gB and LIBRA-seq technology to analyze B cells from seropositive and healthy donors, discovering four prefusion-specific human antibodies binding unique gB epitopes as determined by cryo-EM. Antibodies 5-18 and 3-6 showed strong cross-neutralization against HSV-1 and HSV-2, offering protection in a neonatal mouse model. These findings highlight the molecular and structural determinants of HSV-2 prefusion gB recognition by human antibodies and demonstrate the translational potential of prefusion-specific gB antibodies.

immunology↗

bioRxiv2024

Generation of antigen-specific paired heavy-light chain antibody sequences using large language models

The traditional process of antibody discovery is limited by inefficiency, high costs, and low success rates. Recent approaches employing artificial intelligence (AI) have been developed to optimize existing antibodies and generate antibody sequences in a target-agnostic manner. In this work, we present MAGE (Monoclonal Antibody GEnerator), a sequence-based Protein Language Model (PLM) fine-tuned for the task of generating paired human variable heavy and light chain antibody sequences against targets of interest. We show that MAGE can generate novel and diverse antibody sequences with experimentally validated binding specificity against SARS-CoV-2, an emerging avian influenza H5N1, and respiratory syncytial virus A (RSV-A). MAGE represents a first-in-class model capable of designing human antibodies against multiple targets with no starting template.

bioinformatics↗

bioRxiv2023

Cellular protection from H2O2 toxicity by Fv-Hsp70 and mutants of Fv-Hsp70. Protection via catalase and gamma-glutamyl cysteine synthase.

Heat shock proteins (HSPs), especially Hsp70 (HSPA1), have been associated with cellular protection from various cellular stresses including heat, hypoxia-ischemia, neurodegeneration, toxins, and trauma. Endogenous HSPs are often synthesized in direct response to these stresses but in many situations are inadequate in protecting cells. The present study addresses the transduction of Hsp70 into cells providing protection from acute oxidative stress by H2O2. The recombinant Fv-Hsp70 protein and two mutant Fv-Hsp70 proteins minus the ATPase domain, and minus the ATPase and terminal lid domains were tested at 0.5 and 1.0 uM concentrations after two different concentrations of H2O2 treatment. All three recombinant proteins protected SH-SY5Y cells from acute H2O2 toxicity. This data indicated that the protein binding domain was responsible for cellular protection. In addition, experiments pretreating cells with inhibitors of antioxidant proteins catalase and gamma-glutamylcysteine synthase (GGCS) before H2O2 resulted in cell death despite treatment with Fv-Hsp70, implying that both enzymes were protected from acute oxidative stress after treatment with Fv-Hsp70. This study demonstrates that Fv-Hsp70 is protective in our experiments primarily by the protein-binding domain. The Hsp70 terminal lid domain was also not necessary for protection. Cellular protection was protective via the antioxidant proteins catalase and GGCS.

cell biology↗

bioRxiv2019

Targeting the mTORC2 signaling complex in B cell malignancies.

Hyperactive PI3 kinase-Akt (PI3K-Akt) signaling has an important role in cell growth and resistance to apoptosis in B cell malignancies. Inhibition of this pathway by blocking PI3K activity, and or inhibiting mTORC1/2 signaling complexes is an active area of research in B cell leukemia/lymphoma such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). With a tissue-scan array, the expression of Rictor is a component of the mTORC2 complex was determined by quantitative PCR in a number of B cell malignancies. Rictor was found to be over-expressed in CLL and MCL cells as compared to normal B cells with no over-expression in Hodgkins and non-Hodgkins lymphomas. Inactivation of Rictor was performed by shRNA in two Mantle cell lines and these stable Rictor knockdown cell lines demonstrated a slower growth of cells as compared to scrambled shRNA control. In addition, there was a decrease of mTORC2 signaling and B cell receptor (BCR) cross-linking mediated Akt (Ser473) and NDRG1 (Thr 346) phosphorylation. To specifically disrupt the mTORC2 signaling complex and target Rictor overexpression, previously identified inhibitors that block Rictor and MTOR interaction in a yeast two-hybrid system were analyzed. Treatment of primary CLL specimens with these inhibitors followed by immunoprecipitation experiments confirmed the disruption of the mTORC2 complex. These inhibitors also induced apoptosis in CLL specimens and were more effective than rapamycin, an MTOR inhibitor and pp242, an mTORC1 and 2 inhibitors, at equimolar concentrations. Treatment of CLL specimens with the lead inhibitor, compound#6, resulted in inhibition of p-Akt, p-GSK 3 beta, p-PKC alpha, p-Foxo1, and p-Foxo3, with minimal effect on the phosphorylation of an mTORC1 target gene, S6 kinase. In comparison with Idelalisib (CAL-101), a clinically approved PI3Kinase p110 delta inhibitor in CLL, comp#6 is more effective in inducing apoptosis in primary CLL specimens at equimolar concentrations (mean 51.2, SD 21.7 as compared to mean 26.9, SD 17.2). The data support the effectiveness of these novel inhibitors that specifically disrupt the mTORC2 complex in primary CLL specimens.

cancer biology↗