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Apoptosis, a fundamental process for both human health and disease, is initiated and regulated by protein-protein interactions, notable examples of which are the interactions involving Bcl-2 and IAP protein families. This article discusses recent advances in the use of chemical approaches in discovering and studying small molecules targeted to proteins of the Bcl-2 and IAP families. These small molecules and their complexes with receptors provide the tools and model systems to probe the basic mechanism of molecule recognition underling the life and death of cells and develop novel strategies for therapeutic intervention of the dysregulated apoptotic process. The review of these studies highlights the opportunity and challenge in this emerging area of chemical and chemical biological research. [Copyright &y& Elsevier]

Summary: ARTS (apoptosis-related protein in the TGF-βsignaling pathway) is a mitochondrial protein that binds XIAP (X-linked inhibitor of apoptosis protein) upon entering the cytosol, thus promoting cell death. Expression of ARTS is lost in some malignancies. Here, we show that ARTS binds to XIAP at BIR1, a domain distinct from the caspase-binding sites. Furthermore, ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP. Cells lacking either Siah or ARTS contain higher steady-state levels of XIAP. Thus, ARTS serves as an adaptor to bridge Siah-1 to XIAP, targeting it for destruction. [ABSTRACT FROM AUTHOR]

Summary: Chemokines and their receptors play important roles in numerous physiological and pathological processes. To develop natural chemokines into receptor probes and inhibitors of pathological processes, the lack of chemokine-receptor selectivity must be overcome. Here, we apply chemical synthesis and the concept of modular modifications to generate unnatural synthetically and modularly modified (SMM)-chemokines that have high receptor selectivity and affinity, and reduced toxicity. A proof of the concept was shown by transforming the nonselective viral macrophage inflammatory protein-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for human immunodeficiency virus (HIV)-1 entry. These new analogs provided insights into receptor binding and signaling mechanisms and acted as potent HIV-1 inhibitors. These results support the concept of SMM-chemokines for studying and controlling the function of other chemokine receptors. [Copyright &y& Elsevier]