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Trends Mol Med. 2016 May;22(5):359-76. doi: 10.1016/j.molmed.2016.03.005. Epub 2016 Mar 30.

Abstract

Glucagon-like peptide-1 (GLP-1) analogs are considered the best current medicines for type 2 diabetes (T2D) and obesity due to their actions in lowering blood glucose and body weight. Despite similarities to GLP-1, glucose-dependent insulinotropic polypeptide (GIP) has not been extensively pursued as a medical treatment for T2D. This is largely based on observations of diminished responses of GIP to lower blood glucose in select patients, as well as evidence from rodent knockout models implying that GIP promotes obesity. These findings have prompted the belief in some, that inhibiting GIP action might be beneficial for metabolic diseases. However, a growing body of new evidence - including data based on refined genetically modified models and improved pharmacological agents - suggests a paradigm shift on how the GIP system should be manipulated for metabolic benefits.

Finan B¹, Müller TD¹, Clemmensen C¹, Perez-Tilve D², DiMarchi RD³, Tschöp MH⁴.

Author information

• ¹Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
• ²Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
• ³Department of Chemistry, Indiana University, Bloomington, IN, USA.
• ⁴Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. Electronic address: matthias.tschoep@helmholtz-muenchen.de.

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ChemMedChem. 2016 Sep 6. doi: 10.1002/cmdc.201600288. [Epub ahead of print]

Abstract

The use of peptides in therapy presents several limitations, from physicochemical characteristics to inadequate pharmacokinetic profiles for oral absorption. As peptides are gaining importance in the therapeutic arsenal, there is an increasing need to rationalize the main characteristics of this compound class in the market. Therefore, we performed an extensive analysis of all known peptide drugs and clinical candidates based on their peptide features, physicochemical and structural properties, and correlated these with their administration route and therapeutic classes. Peptide drugs are widely distributed across drug and pharmacological space, covering several therapeutic areas with structural diversity and complexity, distributed between groups of cyclic and linear compounds. Although structural and physicochemical properties are clear within these groups, we counter the consensus that cyclic peptides have better oral availability than linear peptides, as most of the orally administrated peptides have linear structures. This study and review furnishes information that could support peptide drug design, with a new cutoff of known descriptors that go beyond the Rule of Five.

Santos GB¹, Ganesan A², Emery FS³.

Author information

• ¹School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Cafe s/n, Cidade Universitaria, Ribeirao Preto, SP, Brazil.
• ²School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
• ³School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Cafe s/n, Cidade Universitaria, Ribeirao Preto, SP, Brazil. flavioemery@fcfrp.usp.br.

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Chemistry. 2016 Jun 3. doi: 10.1002/chem.201601410. [Epub ahead of print]

Abstract

Human insulin-like peptide-6 (INSL-6) belongs to the insulin superfamily and shares the distinctive disulfide bond configuration of human insulin. In this report we present the first chemical synthesis of INSL-6 utilizing fluorenylmethyloxycarbonyl-based (Fmoc) solid-phase peptide chemistry and regioselective disulfide bond construction protocols. Due to the presence of an oxidation-sensitive tryptophan residue, two new orthogonal synthetic methodologies were developed. The first method involved the identification of an additive to suppress the oxidation of tryptophan during iodine-mediated S-acetamidomethyl (Acm) deprotection and the second utilized iodine-free, sulfoxide-directed disulfide bond formation. The methodologies presented here offer an efficient synthetic route to INSL-6 and will further improve synthetic access to other multiple-disulfide-containing peptides with oxidation-sensitive residues.

Wu F¹, Mayer JP¹, Zaykov AN¹, Zhang F¹, Liu F², DiMarchi RD³.

Author information

• ¹Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA.
• ²Novo Nordisk Research Center Indianapolis, 5225 Exploration Drive, Indianapolis, Indiana, 46241, USA. falx@novonordisk.com.
• ³Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana, 47405, USA. rdimarch@indiana.edu.

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Cell. 2016 Jun 16;165(7):1632-43. doi: 10.1016/j.cell.2016.05.023.

Abstract

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.

Wootten D¹, Reynolds CA², Smith KJ², Mobarec JC², Koole C³, Savage EE⁴, Pabreja K⁴, Simms J⁵, Sridhar R⁴, Furness SG⁴, Liu M⁶, Thompson PE⁶, Miller LJ⁷, Christopoulos A⁴, Sexton PM⁸.

Author information

• ¹Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: denise.wootten@monash.edu.
• ²School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK.
• ³Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
• ⁴Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
• ⁵School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
• ⁶Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
• ⁷Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA.
• ⁸Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: patrick.sexton@monash.edu.

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Nat Chem. 2016 Feb;8(2):120-8. doi: 10.1038/nchem.2413. Epub 2015 Dec 21.

Abstract

Site-selective functionalization of complex molecules is one of the most significant challenges in chemistry. Typically, protecting groups or catalysts must be used to enable the selective modification of one site among many that are similarly reactive, and general strategies that selectively tune the local chemical environment around a target site are rare. Here, we show a four-amino-acid sequence (Phe-Cys-Pro-Phe), which we call the 'π-clamp', that tunes the reactivity of its cysteine thiol for site-selective conjugation with perfluoroaromatic reagents. We use the π-clamp to selectively modify one cysteine site in proteins containing multiple endogenous cysteine residues. These examples include antibodies and cysteine-based enzymes that would be difficult to modify selectively using standard cysteine-based methods. Antibodies modified using the π-clamp retained binding affinity to their targets, enabling the synthesis of site-specific antibody-drug conjugates for selective killing of HER2-positive breast cancer cells. The π-clamp is an unexpected approach to mediate site-selective chemistry and provides new avenues to modify biomolecules for research and therapeutics.

Zhang C¹, Welborn M¹, Zhu T¹, Yang NJ², Santos MS², Van Voorhis T¹, Pentelute BL¹.

Author information

• ¹Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
• ²Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

Source:

Diabetes Care. 2016 Jun 9. pii: dc160046. [Epub ahead of print]

Abstract

OBJECTIVE:

This study assessed the efficacy and safety of LixiLan, a fixed-ratio, titratable, combination of 2 units insulin glargine (Gla-100) and 1 μg lixisenatide administered once daily via a single pen, versus Gla-100 in insulin-naïve type 2 diabetes on metformin.

RESEARCH DESIGN AND METHODS:

Participants were randomized to once-daily LixiLan (n = 161) or Gla-100 (n = 162) for 24 weeks, while continuing metformin. LixiLan and Gla-100 were started at 10 units/5 μg and 10 units, respectively, and titrated based on the Gla-100 requirement according to fasting plasma glucose levels. The primary objective was to test noninferiority (upper bound of the 95% CI ≤0.4%) of LixiLan in reducing HbA_1c; if met, statistical superiority was tested. Secondary objectives included body weight changes, hypoglycemia, and safety.

RESULTS:

Baseline characteristics (mean age 57 years, diabetes duration 6-7 years, BMI 32 kg/m²) were similar between groups. At week 24, mean HbA_1c was reduced from 8.0% (64 mmol/mol) at baseline to 6.3% (45 mmol/mol) and 6.5% (48 mmol/mol) with LixiLan and Gla-100, respectively, establishing statistical noninferiority and superiority of LixiLan (least-squared mean [95% CI] difference: -0.17% [-1.9 mmol/mol] (-0.31, -0.04% [-3.4, -0.4 mmol/mol]; P = 0.01). HbA_1c <7.0% (<53 mmol/mol) was achieved in 84% and 78% of participants (nonsignificant), respectively. LixiLan improved 2-h postmeal plasma glucose versus Gla-100 (least-squared mean difference: -3.17 mmol/L (-57 mg/dL); P < 0.0001). Body weight was reduced with LixiLan (-1 kg) and increased with Gla-100 (+0.5 kg; P < 0.0001), with no increase in hypoglycemic events (∼25% in each group). The incidence of nausea (7.5%) and vomiting (2.5%) was low with LixiLan.

CONCLUSIONS:

LixiLan achieved statistically significant reductions to near-normal HbA_1c levels with weight loss and no increased hypoglycemic risk, compared with insulin glargine alone, and a low incidence of gastrointestinal adverse events in type 2 diabetes inadequately controlled on metformin.

Rosenstock J¹, Diamant M², Aroda VR³, Silvestre L⁴, Souhami E⁴, Zhou T⁵, Perfetti R⁵, Fonseca V⁶; LixiLan PoC Study Group.

Author information

• ¹Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX juliorosenstock@dallasdiabetes.com.
• ²VU University Medical Center, Amsterdam, the Netherlands.
• ³MedStar Health Research Institute, Hyattsville, MD.
• ⁴Sanofi, Paris, France.
• ⁵Sanofi, Bridgewater, NJ.
• ⁶Tulane University Health Sciences Center, New Orleans, LA.

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Future Oncol. 2016 Jun;12(11):1321-9. doi: 10.2217/fon-2015-0054. Epub 2016 Apr 5.

Abstract

E75 (nelipepimut-S) is an immunogenic peptide derived from the HER2 protein. When combined with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF), nelipepimut-S has been used as a vaccine that is capable of eliciting a robust anti-HER2 immune response. Early-phase clinical trials that enrolled women with node-positive or high-risk node-negative breast cancer who had been rendered disease free with standard of care therapy but were at risk for recurrence, demonstrated the vaccine to be safe with a suggestion of clinical benefit. Nelipepimut-S is currently being evaluated in a Phase III clinical trial. This article covers the preclinical and clinical development of nelipepimut-S.

Clifton GT¹, Peoples GE², Mittendorf EA³.

Author information

• ¹Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1484, Houston, TX 77030, USA.
• ²Cancer Vaccine Development Program, Metis Foundation, 600 Navarro Street, San Antonio, TX 78205, USA.
• ³Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1434, Houston, TX 77030, USA.

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Sci Transl Med. 2016 Mar 9;8(329):329ra34. doi: 10.1126/scitranslmed.aad5653.

Abstract

The vast majority of ovarian cancer-related deaths are caused by metastatic dissemination of tumor cells, resulting in subsequent organ failure. However, despite our increased understanding of the physiological processes involved in tumor metastasis, there are no clinically approved drugs that have made a major impact in increasing the overall survival of patients with advanced, metastatic ovarian cancer. We identified prosaposin (psap) as a potent inhibitor of tumor metastasis, which acts via stimulation of p53 and the antitumorigenic protein thrombospondin-1 (TSP-1) in bone marrow-derived cells that are recruited to metastatic sites. We report that more than 97% of human serous ovarian tumors tested express CD36, the receptor that mediates the proapoptotic activity of TSP-1. Accordingly, we sought to determine whether a peptide derived from psap would be effective in treating this form of ovarian cancer. To that end, we developed a cyclic peptide with drug-like properties derived from the active sequence in psap. The cyclic psap peptide promoted tumor regression in a patient-derived tumor xenograft model of metastatic ovarian cancer. Thus, we hypothesize that a therapeutic agent based on this psap peptide would have efficacy in treating patients with metastatic ovarian cancer.

Source:

Nat Chem. 2016 Feb;8(2):120-8. doi: 10.1038/nchem.2413. Epub 2015 Dec 21.

Abstract

Site-selective functionalization of complex molecules is one of the most significant challenges in chemistry. Typically, protecting groups or catalysts must be used to enable the selective modification of one site among many that are similarly reactive, and general strategies that selectively tune the local chemical environment around a target site are rare. Here, we show a four-amino-acid sequence (Phe-Cys-Pro-Phe), which we call the 'π-clamp', that tunes the reactivity of its cysteine thiol for site-selective conjugation with perfluoroaromatic reagents. We use the π-clamp to selectively modify one cysteine site in proteins containing multiple endogenous cysteine residues. These examples include antibodies and cysteine-based enzymes that would be difficult to modify selectively using standard cysteine-based methods. Antibodies modified using the π-clamp retained binding affinity to their targets, enabling the synthesis of site-specific antibody-drug conjugates for selective killing of HER2-positive breast cancer cells. The π-clamp is an unexpected approach to mediate site-selective chemistry and provides new avenues to modify biomolecules for research and therapeutics.