Biosynthetic Strategies for Macrocyclic Peptides

Macrocyclic peptides are predominantly peptide structures bearing one or more rings and spanning multiple amino acid residues. Macrocyclization has become a common approach for improving the pharmacological properties and bioactivity of peptides. A variety of ribosomal-derived and non-ribosomal synthesized cyclization approaches have been established. The biosynthesis of backbone macrocyclic peptides using seven new emerging methodologies will be discussed with regard to the features and strengths of each platform rather than medicinal chemistry tools. The mRNA display variant, known as the random nonstandard peptide integrated discovery (RaPID) platform, utilizes flexible in vitro translation (FIT) to access macrocyclic peptides containing nonproteinogenic amino acids (NAAs). As a new discovery approach, the ribosomally synthesized and post-translationally modified peptides (RiPPs) method involves the combination of ribosomal synthesis and the phage screening platform together with macrocyclization chemistries to generate libraries of macrocyclic peptides. Meanwhile, the split-intein circular ligation of peptides and proteins (SICLOPPS) approach relies on the in vivo production of macrocyclic peptides. In vitro and in vivo peptide library screening is discussed as an advanced strategy for cyclic peptide selection. Specifically, biosynthetic bicyclic peptides are highlighted as versatile and attractive modalities. Bicyclic peptides represent another type of promising therapeutics that allow for building blocks with a heterotrimeric conjugate to address intractable challenges and enable multimer complexes via linkers. Additionally, we discuss the cell-free chemoenzymatic synthesis of macrocyclic peptides with a non-ribosomal catalase known as the non-ribosomal synthetase (NRPS) and chemo-enzymatic approach, with recombinant thioesterase (TE) domains. Novel insights into the use of peptide library tools, activity-based two-hybrid screening, structure diversification, inclusion of NAAs, combinatorial libraries, expanding the toolbox for macrocyclic peptides, bicyclic peptides, chemoenzymatic strategies, and future perspectives are presented. This review highlights the broad spectrum of strategy classes, novel platforms, structure diversity, chemical space, and functionalities of macrocyclic peptides enabled by emerging biosynthetic platforms to achieve bioactivity and for therapeutic purposes.     

A modified square well model in obtaining the surface tension of pure and binary mixtures of hydrocarbons

A model based on the perturbation theory of fluids was proposed to correlate the experimental data for surface tension of pure hydrocarbons in a wide range of temperature. The results obtained for the pure hydrocarbons were directly used to predict the surface tension for binary hydrocarbon mixtures at various temperatures. In the proposed model, a modified form of the square well potential energy between the molecules of the reference fluid was taken into account while the Lennard–Jones dispersion energy was considered to be dominant amongst the molecules as the perturbed term to the reference part of the model. In general, the proposed model has three adjustable parameters which are chain length, m, size, σ, and energy, ε/κ, parameters, but in some cases the number of parameters was reduced to two, thereby setting the chain length to be unity for pure hydrocarbons. The regressed values of these parameters were obtained using the experimental data for pure hydrocarbons at different temperatures. The results showed that these parameters can be related to the molar mass of hydrocarbons. The model was also extended to predict the surface tension of binary hydrocarbon mixtures using the parameters obtained for the pure compounds. It is worth noting that no additional parameter has been introduced into the model in the extension of the model to the mixtures studied in this work. The results showed that the proposed model can accurately correlate the surface tension of pure hydrocarbons. Also the results showed that the surface tension for binary mixture of hydrocarbons can be accurately predicted using the proposed model over a wide temperature range.     

A method for direct simulation of flexible fiber suspensions using lattice Boltzmann equation with external boundary force

The computational method presented here can be used to study the effect of volume fraction and particle deformation on the rheology and microstructure of deformable fibers suspended in Newtonian fluid. In this method, the flow is computed on a fixed regular ‘lattice’ using the lattice Boltzmann method, where each solid particle is mapped onto a Lagrangian frame moving continuously through the domain. Instead of the standard bounce-back method, an external boundary force is used to impose the no-slip boundary condition at the fluid–solid interface for stationary or moving boundaries. The motion and orientation of the fiber are obtained from Newtonian dynamics equations. Although the external boundary force method is general, in this application it is used in conjunction with a flexible fiber model, which calculates the flexible fiber deformation by the real material properties. The methodology is validated by comparing with experimental and theoretical results.     

Solution to radiative transfer equation in a 3-D rectangular enclosure due to discontinuous heat flow divergence

In this paper a new model and computer code is presented by considering singular and discontinuous heat flow divergence. A hybrid model including Smith’s WSGG model and Coppale and Vervish’s model is used for calculating gas radiative properties. Energy equation is solved simultaneously to reach temperature field which specify gas radiative properties. S ₈ order of discrete ordinate method is used to solve RTE. It is assumed that walls of enclosure are gray, diffuse and opaque with specified temperature. Boundary conditions are corrected in each iteration that change temperature field.     

Block liposomes from curvature-stabilizing lipids: connected nanotubes, -rods, or -spheres

We report on the discovery of block liposomes, a new class of chain-melted (liquid) vesicles, with membranes comprised of mixtures of the membrane-curvature-stabilizing multivalent lipid MVLBG2 of colossal charge +16 e and neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). In a narrow MVLBG2 composition range (8-10 mol%), cryo-TEM revealed block liposomes consisting of distinctly shaped, yet connected, nanoscale spheres, pears, tubes, or rods. Unlike typical liposome systems, where spherical vesicles, tubular vesicles, and cylindrical micelles are separated on the macroscopic scale, within a block liposome, shapes are separated on the nanometer scale. Diblock (pear-tube) and triblock (pear-tube-pear) liposomes contain nanotubes with inner lumen diameter of 10-50 nm. Diblock (sphere-rod) liposomes were found to contain micellar nanorods approximately 4 nm in diameter and several micrometers in length, analogous to cytoskeletal filaments of eukaryotic cells. Block liposomes may find a range of applications in chemical and nucleic acid delivery and as building blocks in the design of templates for hierarchical structures.     

Optimal repair allocation in a series system expected discounted operation time criterion

Consider a series system with n repairable components maintained by a single repairman. The following assumptions are made. Component failure and repair times are independent, exponentially distributed, random variables. Component failures can occur even while the system is not functioning and it is possible to reassign the repairman among failed components instantaneously. It is shown that the policy which always assigns the repairman to the failed component with the smallest failure rate among the failed ones maximizes the expected discounted system operation time irrespective of the values of the repair rates and the discount rate     

Extension of the volume-of-fluid method for analysis of free surface viscous flow in an ideal gas

The volume-of-fluid (VOF) method is a simple and robust technique for simulating free surface flows with large deformations and intersecting free surfaces. Earlier implementations used Laplace's formula for the normal stress boundary condition at the interface between the liquid and vapour phases. We have expanded the interfacial boundary conditions to include the viscous component of the normal stress in the liquid phase and, in a limited manner, to allow the pressure in the vapour phase to vary. Included are sample computations that show the accuracy of added third-order-accurate differencing schemes for the convective terms in the Navier-Stokes equation (NSE), the viscous terms in the normal stress at the interface and the solution of potential flow in the vapour phase coupled with the solution of the NSE in the liquid phase. With these modifications we show that the VOF method can accurately predict the instability of a thin viscous sheet flowing through a stagnant vapour phase.     

A New Method for Analysis of the Fluid Interaction with a Deformable Membrane

The lattice Boltzmann cellular automaton method has been successfully extended for analysis of fluid interactions with a deformable membrane or web. The hydrodynamic forces on the solid web are obtained through computation of the fluid flow stress at the moving boundary using the lattice Boltzmann method. Analysis of solid boundary deformation or vibration due to hydrodynamic force is based on Newtonian dynamics and a molecular dynamic type approach.     

Mammalian alkaloids: Synthesis and O-methylation of (S)- and (R)-3′-hydroxycoclaurine and their N-methylated analogues with S-adenosyl-L-[methyl-14C]methionine in presence of mammalian catechol O-methyltransferase

O-Methylation of the optically active 3′-hydroxycoclaurines 3a and 3b and of the N-methylated analogs 5a,b with S-adenosyl-L -[methyl-¹⁴C]methionine in presence of mammalian COMT was investigated in vitro. The N-unsubstituted (1S)- and (1R )-isomers 3a and 3b , respectively, afforded almost equal amounts of the corresponding N-norreticuline 4 and N-nororientaline 19 , besides two unknown by-products (see Fig. and Table 1). The N-methylated (1S)-isoquinoline 5a , on the other hand, afforded largely (S)-orientaline ((S)- 19 ), while an almost equal mixture of (R)-reticuline ( 6b ) and (R)-orientaline ((R)- 19 ) was obtained from the (1R)-enantiomer 5b . The isoquinolines 3a,b and 5a,b were prepared by a Bischler-Napieralski cyclization yielding O-benzyl-protected isoquinoline 10 (Scheme 1). The optical resolution of 10 was accomplished with 2′-bromotartranilic acid. The N-methylated isoquinolines were prepared by N-formylation of 10a,b and reduction of the formamides 13a,b with diborane (→ 14a,b ). Deblocking of the benzyl-ether moieties of 10a,b and 14a,b was accomplished by catalytic hydrogenation in presence of HCl, affording directly 3a,b ·HCl and 5a,b ·HCl, respectively.