The design of low-molecular-weight ligands (< 750 Da) that recognize protein surfaces and subsequently disrupt protein± protein interactions is an area of intense research. [1] Current strategies for identifying small-molecule protein-surface antagonists primarily involve the use of combinatorial methods.

Simple peptidomimetic molecules derived from amino acids were reacted with meta- and para-bis(bromomethyl)benzene in acetonitrile to very efficiently yield macrocyclic structures. The cyclization reaction does not require high dilution techniques and seems to be insensitive to the size of the formed macrocycle. The analysis of data obtained by (1)H NMR, single-crystal X-ray diffraction, fluorescence measurements, and molecular mechanics indicate that folded conformations can preorganize the system for an efficient cyclization. The role played by intramolecular hydrogen-bonding and solvophobic effects in the presence of folded conformations is analyzed.

The design of low-molecular-weight ligands (< 750 Da) that recognize protein surfaces and subsequently disrupt protein± protein interactions is an area of intense research. [1] Current strategies for identifying small-molecule protein-surface antagonists primarily involve the use of combinatorial methods.

Split personality: A series of oligoamide‐based helix mimetics bind to a complementary helical motif in Islet amyloid polypeptide (IAPP), a protein implicated in the pathology of type II diabetes. These compounds accelerated IAPP amyloid formation under lipid‐free conditions, but inhibited it under lipid‐catalyzed conditions. hIAPP=human IAPP.

A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X L , and Mcl-1, which bind to the BH3 ␣-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 ␣-helical mimetic BH3-M6 that binds to Bcl-X Apoptosis, a form of programmed cell death, is a highly conserved process in all multicellular organisms and is essential for embryonic development and adult tissue homeostasis. Deregulation of apoptosis contributes to several diseases including cancer (1). Apoptosis is primarily controlled by two major pathways, namely the death receptor (extrinsic) and the mitochondrial (intrinsic) pathways (2). The former is mediated by members of the tumor necrosis factor (TNF) 6 receptor superfamily, while the latter largely depends on multiple Bcl-2 family proteins, which affect the integrity of the mitochondrial outer membrane (MOM) (3). Both pathways converge on common cysteine proteases of the caspase family, which are responsible for the execution of apoptosis (4).The Bcl-2 family consists of anti-apoptotic and pro-apoptotic proteins. Anti-apoptotic proteins, such as Bcl-2, Bcl-X L , Bcl-w, Mcl-1, and Bfl-1 (Bcl-2A1) contain four Bcl-2 homology (BH) domains, while the pro-apoptotic members are divided into proteins with three BH domains BH1-BH3 (Bax, Bak, and Bok), and proteins with only a BH3 domain (e.g. Bim, Bad, Bik, Bmf, Bid, Noxa, and Puma) (5). Multi-domain proapoptotic proteins Bax and Bak are absolutely required for apoptosis (2). In response to cellular stress, they induce the release from mitochondria of apoptogenic factors such as cytochrome c, which then cooperate with APAF-1 to induce caspase-9 activation, followed by caspase-mediated apoptosis (6). BH3-only proteins act upstream of Bax and Bak and are important for the initiation of apoptosis. Importantly, the BH3 domain is essential for the killing function of pro-apoptotic proteins (7).An important feature of the Bcl-2 proteins is that they can homo-and heterodimerize, giving rise to three competing, but not necessarily exclusive models that could explain how the balance between pro-and anti-apoptotic proteins regulates apoptosis (7). For instance, upon receiving an apoptotic signal, BH3-only proteins directly or indirectly induce Bax and Bak activation and homo-oligomerization in the MOM, which is thought to be responsible for MOM permeabilization, resulting in the release of cytochrome c and the initiation of intrinsic apoptosis. However, activated Bax and Bak still can be kept in check by binding to anti-apoptotic Bcl-2 proteins (8 -10). X-ray diffraction and nuclear magnetic resonance (NMR) studies have shown that the amphipathic ␣-helices of pro-apoptotic proteins such as Bak or Bad BH3 domains fit into a hydrophobic pocket formed by the BH1, BH2, * This work was funded, in whole or in part, by National Institutes of Health P01 Grants CA118210 and GM69850.