Macrocycles and constrained peptides, generally defined as cyclic small molecules or peptides of 500–2,000 Da, have undergone a rebirth over the last five years in drug discovery, due mainly to the introduction of new approaches for their synthesis and screening. This scientific progress has fueled a burst of business activity, with at least 12 biotech companies in the space, of which almost half were founded in the last 5 years.
This special collection from SciBX: Science-Business eXchange provides an overview of the state of the field from both the scientific and the business perspective.
First, in a SciBX Analysis, a roadmap for progress across various platforms is laid out by the participants at a recent SciBX Summit on macrocycles and constrained peptides. The article identifies four areas of science in which work is needed to enable innovation in the field: pharmacokinetics, cell permeability, oral bioavailability and target engagement to develop more drug-like compounds and streamline drug discovery.
This Analysis is complemented by a BioCentury Product Discovery and Development piece that provides a comprehensive overview of the competitive landscape by laying out the players in the field, their partnerships and the status of their most advanced programs.
Next, we provide an introduction to an interactive dashboard produced by Relay Technology Management that allows users to explore trends in grants, publications, company pipelines, transactions and IP relevant to macrocycles and constrained peptides. Relay TM is a strategic partner of Nature Research.
This is followed by a Review by White and Yudin that revisits the latest developments in peptide macrocyclization strategies. The cyclization of macrocycles using traditional chemical synthesis approaches has faced enormous challenges due to steric constraints and the unwieldiness of small and large precursors. But recently, new solutions have emerged, including versatile platforms for macrocycle library generation that open a myriad of new opportunities for generating synthetic macrocycles. A second SciBX Analysis specifically explores the technical and commercial possibilities that may open up based on a new method for creating large libraries of N-methylated peptide macrocycles developed by Suga and collaborators.
Finally, an article by Stewart et al. illustrates the potential of a particular class of constrained peptides called stapled peptides as therapeutic agents. Harnessing the binding precision of stapled peptides, the authors were able to design a highly specific inhibitor of MCL-1, a critical survival factor in a wide range of human cancers.
The Analyses, Reviews and Articles presented here provide a broad overview of the scientific and business status of the field and some examples of specific technological advances that are but a small sample of the possibilities to come.
We acknowledge the support of Aileron Therapeutics Inc., PolyPeptide Group, Polyphor Ltd. and Lanthio Pharma B.V. in producing this collection. Nature Research and BioCentury Publications Inc. have sole responsibility for editorial content
April 2013
Science-Business eXchange
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by Elena Dolghih and Matthew P. Jacobson
In order to reach their pharmacologic targets, successful central nervous system (CNS) drug candidates have to cross a complex protective barrier separating brain from the blood. Being able to predict a priori which molecules can successfully penetrate this barrier could be of significant value in CNS drug discovery. Herein we report a new computational approach that combines two mechanism-based models, for passive permeation and for active efflux by P-glycoprotein, to provide insight into the multiparameter optimization problem of designing small molecules able to access the CNS. Our results indicate that this approach is capable of distinguishing compounds with high/low efflux ratios as well as CNS+/CNS– compounds and provides advantage over estimating P-glycoprotein efflux or passive permeability alone when trying to predict these emergent properties. We also demonstrate that this method could be useful for rank-ordering chemically similar compounds and that it can provide detailed mechanistic insight into the relationship between chemical structure and efflux ratios and/or CNS penetration, offering guidance as to how compounds could be modified to improve their access into the brain.
December 2, 2012
ACS Chemical Neuroscience
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by Rand AC, Leung SS, Eng H, Rotter CJ, Sharma R, Kalgutkar AS, Zhang Y, Varma MV, Farley KA, Khunte B, Limberakis C, Price DA, Liras S, Mathiowetz AM, Jacobson MP, Lokey RS
A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats. In particular, the ionization state of the peptide was examined by the incorporation of naturally occurring amino acid residues that are charged in differing regions of the gut. In addition, data was generated in a variety of in vitro assays and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed.
October 3, 2012
Medicinal Chemical Communications
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Macrocycles in New Drug Discovery
by Jamie Mallinson and Ian Collins
The use of drug-like macrocycles is emerging as an exciting area of medicinal chemistry, with several recent examples highlighting the favorable changes in biological and physicochemical properties that macrocyclization can afford. Natural product macrocycles and their synthetic derivatives have long been clinically useful and attention is now being focused on the wider use of macrocyclic scaffolds in medicinal chemistry in the search for new drugs for increasingly challenging targets. With the increasing awareness of concepts of drug-likeness and the dangers of ‘molecular obesity’, functionalized macrocyclic scaffolds could provide a way to generate ligand-efficient molecules with enhanced properties. In this review we will separately discuss the effects of macrocyclization upon potency, selectivity and physicochemical properties, concentrating on recent case histories in oncology drug discovery. Additionally, we will highlight selected advances in the synthesis of macrocycles and provide an outlook on the future use of macrocyclic scaffolds in medicinal chemistry.
August 2, 2012
Future Medical Chemistry
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by Leung SS, Mijalkovic J, Borrelli K, Jacobson MP
The biophysical basis of passive membrane permeability is well-understood, but most methods for predicting membrane permeability in the context of drug design are based on statistical relationships that indirectly capture the key physical aspects. Here, we investigate molecular mechanics-based models of passive membrane permeability and evaluate their performance against different types of experimental data, including parallel artificial membrane permeability assays (PAMPA), cell-based assays, in vivo measurements, and other in silico predictions. The experimental data sets we use in these tests are diverse, including peptidomimetics, congeneric series, and diverse FDA approved drugs. The physical models are not specifically trained for any of these data sets; rather, input parameters are based on standard molecular mechanics force fields, such as partial charges, and an implicit solvent model. A systematic approach is taken to analyze the contribution from each component in the physics-based permeability model. A primary factor in determining rates of passive membrane permeation is the conformation-dependent free energy of desolvating the molecule, and this measure alone provides good agreement with experimental permeability measurements in many cases. Other factors that improve agreement with experimental data include deionization and estimates of entropy losses of the ligand and the membrane, which lead to size-dependence of the permeation rate.
June 25, 2012
Journal of Chemical Information and Modeling
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by Rafi SB, Hearn BR, Vedantham P, Jacobson MP, Renslo AR
We evaluate experimentally and computationally the membrane permeability of matched sets of peptidic small molecules bearing natural or bioisosteric unnatural amino acids. We find that the intentional introduction of hydrogen bond acceptor-donor pairs in such molecules can improve membrane permeability while retaining or improving other favorable drug-like properties. We employ an all-atom force field based method to calculate changes in free energy associated with the transfer of the peptidic molecules from water to membrane. This computational method correctly predicts rank order experimental permeability trends within congeneric series and is much more predictive than calculations (e.g., clogP) that do not consider three-dimensional conformation.
April 12, 2012
Journal of Medicinal Chemistry
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by White TR, Renzelman CM, Rand AC, Rezai T, McEwen CM, Gelev VM, Turner RA, Linington RG, Leung SS, Kalgutkar AS, Bauman JN, Zhang Y, Liras S, Price DA, Mathiowetz AM, Jacobson MP, Lokey RS
Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat.
September 25, 2011
Nature Chemical Biology
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by Elena Dolghih, Clifford Bryant, Adan R. Renslo, Matthew P. Jacobson
P-glycoprotein (P-gp) is an ATP-dependent transport protein that is selectively expressed at entry points of xenobiotics where, acting as an efflux pump, it prevents their entering sensitive organs. The protein also plays a key role in the absorption and blood-brain barrier penetration of many drugs, while its overexpression in cancer cells has been linked to multidrug resistance in tumors. The recent publication of the mouse P-gp crystal structure revealed a large and hydrophobic binding cavity with no clearly defined sub-sites that supports an “induced-fit” ligand binding model. We employed flexible receptor docking to develop a new prediction algorithm for P-gp binding specificity. We tested the ability of this method to differentiate between binders and nonbinders of P-gp using consistently measured experimental data from P-gp efflux and calcein-inhibition assays. We also subjected the model to a blind test on a series of peptidic cysteine protease inhibitors, confirming the ability to predict compounds more likely to be P-gp substrates. Finally, we used the method to predict cellular metabolites that may be P-gp substrates. Overall, our results suggest that many P-gp substrates bind deeper in the cavity than the cyclic peptide in the crystal structure and that specificity in P-gp is better understood in terms of physicochemical properties of the ligands (and the binding site), rather than being defined by specific sub-sites.
June 23, 2011
PLOS – Computational Biology
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by Combs DJ, Lokey RS
Peptoids (N-substituted polyglycines) represent a class of bioinspired oligomers that have unique physical and structural properties. Here we report the construction of “extended peptoids” based on aromatic building blocks, in which the N-alkylaminoacetyl group of the peptoid backbone has been replaced by an N-alkylaminomethylbenzoyl spacer. Both meta- and para-bromomethylbenzoic acids were synthesized, providing access to a new class of peptoids. Further, inclusion of hydrophilic side chains confers water solubility to these compounds, showing that, like simple peptoids, extended peptoids add an extra dimension to synthetic polyamide oligomers with potential application in a variety of biological contexts.
April 9, 2007
Tetrahedron Letters
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