Xin Zhang

Bio: Xin Zhang is an academic researcher from University of Pennsylvania. The author has contributed to research in topics: Virus & Transfection. The author has an hindex of 5, co-authored 7 publications receiving 354 citations.

Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo.

Abstract: Monoclonal antibodies specific for the p185HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185HER2/neu-expressing human cancers. We have used a structure-based approach to develop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar to an anti-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185HER2/neu-expressing tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to apoptosis when used in conjunction with ionizing radiation or chemotherapeutic agents. A comparison of the molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed generally similar activities. The structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies.

Synthetic CD4 exocyclics inhibit binding of human immunodeficiency virus type 1 envelope to CD4 and virus replication in T lymphocytes

Abstract: CD4 functions as a major T-cell surface receptor for human immunodeficiency virus by binding the human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 with relatively high affinity. We have developed constrained aromatically modified analogs of the secondary structures of the first domain of CD4 in order to analyze surfaces involved in binding of gp120. Complementarity determining-like regions (CDRs) of the D1 domain of CD4 were reproduced as synthetic aromatically modified exocyclic (AMEs) forms. The exocyclic CDR3.AME(82-89), derived from the CDRS (residues 82-89) region of CD4 D1 domain, specifically inhibited binding of recombinant gp120 to both recombinant soluble CD4, and CD4+ Jurkat cells, and blocked syncytium formation and virus particle production caused by HIV-1 infection. We have previously shown that the CDR3.AME analog binds to the CD4 CDR3 region and creates a disabled CD4 heterodimer. We propose that the AME prevents the formation of an essential homodimeric surface needed for efficient HIV binding. Additionally the disabled CD4 receptor may be less able to signal the cell to allow HIV replication and HIV infection. Such compounds may represent a new receptor specific approach to modulate biological functions.

Synthetic CD4 exocyclic peptides antagonize CD4 holoreceptor binding and T cell activation.

Abstract: We have developed peptide analogs to analyze precise human CD4 substructures involved in MHC class II binding. Forms of the complementarity determining-like regions (CDRs) of the D1 domain of human CD4 were reproduced as synthetic aromatically modified exocyclic (AME) analogs and tested for their ability to block CD4-MHC II interactions and T cell activation. The exocyclic derived from CDR3 (residues 82-89) of human CD4, which specifically associated with CD4 on the T cell surface to create a heteromeric CD4 complex, blocked IL-2 production and antagonized the normal function of the CD4 receptor. The approach of creating novel synthetic antagonistic receptor complexes may represent a new receptor specific pharmaceutical approach to modulate biological function.

Relationship of p215BRCA1 to tyrosine kinase signaling pathways and the cell cycle in normal and transformed cells.

Abstract: We have analysed the relationship of the products of two genes, neu and BRCA1, known to be important in human breast cancer. Highly specific antibodies that recognized both the rodent and human form of the BRCA1 gene product (Mr 215 kDa, p215BRCA1) were developed to facilitate these efforts. p215BRCA1 was identified as a tyrosine phosphorylated protein primarily localized in the nucleus of several breast cancer cell lines. In transformed murine and human cells, levels of p215BRCA1 tyrosine phosphorylation were inversely correlated with the activity of the erbB family receptor-tyrosine-kinases and with the transformed growth features of these cells. Regulation of p215BRCA1 tyrosine phosphorylation was also related to events in the cell cycle. Increased levels of p215BRCA1 phosphotyrosine content were observed in NIH3T3 cells arrested at the G2/M transition. These findings indicate that the products of BRCA1, neu, and erbB breast cancer genes participate in a common or shared signaling pathway important in cell growth and its regulation.

The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.

Abstract: Homeostasis of multicellular organisms is critically dependent on the correct interpretation of the plethora of signals which cells are exposed to during their lifespan. Various soluble factors regulate the activation state of cellular receptors which are coupled to a complex signal transduction network that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in a variety of pathophysiological phenomena. The aim of this review is to give a broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention. Since the EGFR and HER2 were recently identified as critical players in the transduction of signals by a variety of cell surface receptors, such as G-protein-coupled receptors and integrins, our special focus is the mechanisms and significance of the interconnectivity between heterologous signalling systems.

ErbB receptors: from oncogenes to targeted cancer therapies

Abstract: Understanding the genetic origin of cancer at the molecular level has facilitated the development of novel targeted therapies. Aberrant activation of the ErbB family of receptors is implicated in many human cancers and is already the target of several anticancer therapeutics. The use of mAbs specific for the extracellular domain of ErbB receptors was the first implementation of rational targeted therapy. The cytoplasmic tyrosine kinase domain is also a preferred target for small compounds that inhibit the kinase activity of these receptors. However, current therapy has not yet been optimized, allowing for opportunities for optimization of the next generation of targeted therapy, particularly with regards to inhibiting heteromeric ErbB family receptor complexes.