No abstract

Two families of peptides that specifically bind the extracellular domain of the human type I interleukin 1 (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-la to the type I IL-1 receptor with IC5o values of 45-140 ,uM. Affinity-selective screening of variants of these peptides produced ligands of much higher affinity (IC50 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist.

Both the solution and polymer-supported synthesis of 4-thiazolidinones and 4-metathiazanones derived from amino acids are described. Solution studies showed that moderate to high yields of 4-thiazolidinones could be obtained from the one-pot, three-component condensation of amino acid esters (glycine, alanine, /3-alanine, phenylalanine, and valine), an aldehyde (benzaldehyde, o-tolualdehyde, m-tolualdehyde, p-tolualdehyde, and 3-pyridinecarboxaldehyde), and an a-mercapto carboxylic acid (thiolactic and mercaptoacetic acid). Acylation of standard peptide synthesis resins with an Fmoc-protected amino acid, followed by deprotection of the Fmoc group and condensation with aldehydes and an a-mercapto or /3-mercapto carboxylic acid, lead to the formation of the fiveand six-membered heterocycles. The stepwise assembly of 4-thiazolidinones by treatment of the intermediate imine with an a-mercapto carboxylic acid was also demonstrated. Cleavage from the support under acidic (trifluoroacetic acid) conditions gave high yields and high purities of the liberated 4-thiazolidinones and lower yields of 4-metathiazanones.

Further investigations towards novel glycopeptide/b-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Grampositive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and b -lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28ϳ36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.Keywords multivalent, multivalency, bifunctional, blactam, glycopeptide, antibiotic, MRSA, TD-1792 IntroductionThe medical community is increasingly concerned by the incidence of multi-drug resistant bacterial infection. natural systems; for example, in controlling cell-cell interactions and in the adhesion of a virus particle to an erythrocyte [4]. Recent literature suggests that multivalency may also find applicability in the design of small molecule ligands [5]. Homodimers and oligomers of vancomycin [6], paclitaxel [7] and opioids [8] have all been reported to enhance binding relative to their constitutive monomeric components [9]. In addition to enhanced efficacy it has been proposed that multivalent molecules may also offer physicochemical advantages and allow coupling of pharmacophores with distinct mechanisms of action [10].We previously reported the discovery of compound 1 which was designed to link a vancomycin synthon (attachment point through the vancosamine amino group) with a specific cephalosporin, b-lactam motif (attachment through the C3 pyridinium substituent) using a simple diamide linear alkyl linkage. This compound exhibited excellent potency against a range of Gram-positive pathogens (Table 1) and displayed rapid bactericidal activity against S. aureus ATCC 33591 (MRSA), achieving a 3-log CFU/ml reduction after only 4 hours at a concentration of 0.5 mg/ml.In this paper, we describe further efforts to explore and optimize our multivalent approach to antibacterial drug discovery and report structure activity relationships with regard to the attachment points to both the glycopeptide and b-lactam components. Multivalent DesignConsideration of the central vancomycin (V) core 2 used to construct heterodimer 1 revealed a number of potential attachment points, Fig. 1. In addition to modification of the vancosamine amino group (V V ) [2], vancomycin 2 can be selectively derivatized through the carboxyl terminus (V C ) or the 4Ј, resorcinol-like (...

No abstract