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MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-gamma that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-gamma agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-gamma target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-gamma agonists, MBX-102 displays differential interactions with the PPAR-gamma ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-gamma or alpha/gamma agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-gamma modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-gamma side effects and may represent the next generation insulin sensitizer.

Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-␥ modulator (SPPAR␥M). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-␥. Reporter assays show that HA is a partial PPAR-␥ agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-␥-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/ fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPAR␥M with promising therapeutic utility with the potential for less weight gain. Diabetes

The relentless growth of multidrug resistance and generation of recalcitrant biofilm are major obstacles in treating wounds, particularly in austere military environments where broad-spectrum pathogen coverage is needed. Designed antimicrobial peptides (dAMPs) are constructed analogs of naturally occurring AMPs that provide the first line of defense in many organisms. RP557 is a dAMP resulting from iterative rational chemical structural analoging with endogenous AMPs, human cathelicidin LL-37 and Tachyplesin 1 and the synthetic D2A21 used as structural benchmarks. RP557 possesses broad spectrum activity against Gram-positive and Gram-negative bacteria and fungi, including recalcitrant biofilm with substantial selective killing over bacterial cells compared to mammalian cells. RP557 did not induce resistance following chronic passages of Pseudomonas aeruginosa and Staphylococcus aureus at subinhibitory concentrations, whereas concurrently run conventional antibiotics, gentamycin, and clindamycin, did. Furthermore, RP557 was able to subsequently eliminate the generated gentamycin resistant P. aeruginosa and clindamycin resistant S. aureus strains without requiring an increase in minimum inhibitory concentration (MIC) concentrations. RP557 was evaluated further in a MRSA murine wound abrasion infection model with a topical application of 0.2% RP557, completely eliminating infection. If these preclinical results are translated into the clinical setting, RP557 may become crucial for the empirical broad-spectrum treatment of wound pathogens, so that infections can be reduced to a preventable complication of combat-related injuries.

PurposeTo limit corneal damage and potential loss of vision, bacterial keratitis must be treated aggressively. Innovation in antimicrobials is required due to the need for empirical treatment and the rapid emergence of bacterial resistance. Designed host defense peptides (dHDPs) are synthetic analogues of naturally occurring HDPs, which provide defense against invading pathogens. This study investigates the use of novel dHDPs for the treatment of bacterial keratitis.MethodsThe minimum inhibitory concentrations (MICs) were determined for dHDPs on both Gram-positive and -negative bacteria. The minimum biofilm eradication concentrations (MBEC) and in vitro time-kill assays were determined. The most active dHDP, RP444, was evaluated for propensity to induce drug resistance and therapeutic benefit in a murine Pseudomonas aeruginosa keratitis model.ResultsDesigned HDPs were bactericidal with MICs ranging from 2 to >64 μg/mL and MBEC ranging from 6 to 750 μg/mL. In time-kill assays, dHDPs were able to rapidly reduce bacterial counts upon contact with as little as 2 μg/mL. RP444 did not induce resistance after repeated exposure of P. aeruginosa to subinhibitory concentrations. RP444 demonstrated significant efficacy in a murine model of bacterial keratitis as evidenced by a significant dose-dependent decrease in ocular clinical scores, a significantly reduced bacterial load, and substantially decreased inflammatory cell infiltrates.ConclusionsInnovative dHDPs demonstrated potent antimicrobial activity, possess a limited potential for development of resistance, and reduced the severity of murine P. aeruginosa keratitis. These studies demonstrate that a novel dHDP may have potential to treat patients with sight-threatening bacterial keratitis.