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The limit to product yield in biotechnology is reached at 500 - 800 mg/l fermentation broth. However, if large quantities of proteins are required for products which have to be marketed as quickly as possible, biotechnology remains the technology of choice. Challenging biotechnology, transgenic manufacturing processes use animals or plants with a productivity of up to 20 g/l. Whereas animal transgenic technology still risks potential contaminantion with prions, transgenic plants offer a rather safer manufacturing technology. Since glycosylation of the protein is specific to the production organism from the onset of product development, it must be decided whether the therapeutically active protein should be produced by mammalian cell culture, transgenic animal or transgenic plant. This, however, requires a decision on the manufacturing technology, prior to the knowledge of dose and potential market.
Pegylation, the technology of polyethylene glycol (PEG) conjugation, holds significant promise in maintaining effective plasma concentrations of systemically administered drugs that might otherwise be hampered in vivo by a number of factors, such as rapid elimination by the kidneys. Mobile, nontoxic PEG chains can be conjugated to biotherapeutics, increasing their hydrodynamic volume, which can in turn prolong their plasma retention time, increase their solubility, and shield antigenic determinants on the drug from detection by the immune system. Attaching PEG molecules for optimal pharmacokinetics without obstructing the active sites that are essential for drug efficacy is a major challenge in pegylation. Current pegylation technology uses linkerless conjugation methods to produce coupling without added toxicity or immunogenicity, and may keep the innate surface charge of the pegylated molecule intact. In addition to controlling the size and complexity of PEG molecules, the attachment site can be manipulated to avoid steric hindrance of the drug's active receptor-recognition or substrate-interaction site. A few pegylated drugs have been engineered to have an improved pharmacokinetic profile with preserved bioactivity. They often have prolonged steady plasma concentrations in vivo, thereby making a reduced number of doses possible. Other interesting effects have also emerged, such as the self-regulating pharmacokinetics of pegfilgrastim, a pegylated version of the granulocyte colony-stimulating factor filgrastim that is administered for management of chemotherapy-induced neutropenia. The improved dosing schedule, with longer intervals between administrations of the pegylated agents, will improve compliance and quality of life in patients with chronic disease.
The discovery of new antimicrobial and anticancer drugs, and overcoming the problem of resistance to current anti-infective and anticancer drug therapies require innovation in the pharmaceutical and scientific research community. A further challenge of drug design is to make the therapeutic agent specific, long lasting, of minimal toxicity, and affordable. Microbial and cancer cell surfaces present molecular features that can differentially prefocus drugs within the human host. This property can localize drugs near cell-surface targets, thereby reducing opportunities for adverse effects, or the emergence of drug resistance caused by intracellular drug and target modification and by the induction of drug efflux pumps. The solubility demands on cell-surface targeting drugs should also be less stringent than for those drugs requiring transmembrane transport or internalization in order to reach intracellular targets. Cationic peptides have provided an increasingly important research focus in this regard. Although the cationic antimicrobial peptides are distributed widely in nature and provide localized primary defenses against microbial attack, the susceptibility of L-peptides to proteolysis and the known properties of successful antimicrobials have led to a focus on circularized peptides, D,L-peptides, and peptides containing unusual amino acids. New on the scene as lead antifungal agents are D-octapeptides and their derivatives that were developed from a combinatorial library produced through solid-phase peptide synthesis protocols. These peptides contain an amidated C-terminal tri-arginine motif, which confers membrane impermeability and focuses the peptides near the fungal cell surface. To date, the octapeptides and their derivatives also require some aromaticity, preferably the indole ring of tryptophan. In some cases, a single 4-methoxy-2,3,6-trimethylbenzenesulfonyl moiety remaining on the peptide after incomplete cleavage of the peptide from the solid phase produces a peptide with activity, whereas the parent shows little or no activity in the screen. Recent research advances that support the polycationic cell surface approach include the RGD (Arg-Gly-Asp) tripeptide and its mimetics, as well as aminoglycoside arginine drugs (e.g. neomycin coupled to small arginine polymers) and prodrugs. In the case of polycationic peptides, D-peptides could be used for intravenous injection and direct-surface drug applications, but mimetics will probably be needed for oral delivery.
Potentiometric detection with poly(vinyl chloride) (PVC) based liquid membrane electrode coatings is presented for a series of eighteen beta-adrenoceptor binding drugs (five agonists and thirteen antagonists) in cation exchange-HPLC and RP-HPLC systems. Incorporation of lipophilic cation-exchanger tetrakis(p-chlorophenyl)borate (TCPB) alone or in combination with trioctylated alpha-cyclodextrin into the polymeric liquid membrane gives very sensitive responses for racemic forms of bufuralol, propranolol, carazolol, clenbuterol, mabuterol, cimaterol, bisoprolol, oxprenolol, alprenolol, tertatolol, and bevantolol, especially in the cation-exchange HPLC system applying acetonitrile -- 40 mM phosphoric acid (15: 85, v/v, pH* = 2.35) as the mobile phase. In both applied orthogonal HPLC modes we observed that use of TCPB containing electrodes (no addition of neutral macrocyclic ionophores) gives more than five fold improvement in limit of detection down to 10(-7) M for mabuterol, bufuralol, alprenolol and tertatolol in comparison with UV detection. These results suggest that potentiometric detection, especially in RP-HPLC employing hybrid polymer-silica packings, can be considered as the promising alternative in the high-throughput drug abuse or doping control procedures of investigated beta-adrenergic agonists and beta-adrenolytics in humans and animals. The quantitative structure - potentiometric response relationships were developed for a set of eighteen beta-adrenenergic drugs and a set of PVC based electrodes using TCPB alone or in admixture with trioctylated alpha-cyclodextrin, dibenzo-18-crown-6 or calix[6]arene hexaethylacetate ester. A multiple linear regression model based on computationally derived set of molecular descriptors was used to predict detection limits of beta-blocking agents and beta-adrenergic agonists from their molecular structure in the developed potentiometric detectors. Principal components analysis (PCA) of data considering determined potentiometric detection limits revealed that it can be used to establish a reliable pharmacological classification of compounds with beta-adrenoceptor activity, especially for the differentiation of cardioselective and non-cardioselective beta1-antagonists.
Small research-based pharmaceutical start-ups often lack the budget and do not have the infrastructure available to apply all possible techniques for compound selection. This review details our use of a range of techniques such as high-throughput docking and similarity searching to maximize the success rate when attempting to identify pharmaceutically relevant ligands in a resource-constrained environment.