Macromolecules - proteins, nucleic acids, and polysaccharides - are . He has authored a number of articles, and business analysis/market. Scope of review: This review summarizes the current knowledge of protein and nucleic acid interactions with water, with a special focus on the biomolecular. This dataset provides the information on relationships between concepts or atoms known to the Metathesaurus for the semantic type "Amino Acid Peptide or .
Experiments should be designed to explore how third base redundancy influences protein folding. With such data, the in- formation from a hypothetical protein design could be used to properly construct the DNA of a gene.
A proper gene would then transcribe and translate properly to yield a polypeptide that folds properly. If these conditions were met, the design cycle abstraction would be as shown In Figure If the information flow around the protein design and imple- mentation cycle is preserved, then it should be possible for protein engineers to rapidly traverse this cycle in the design and perfection of novel proteins. His work was the first time that a computer, a PDP-1 from the then-infant Digital Equips ment Corporation DECwas used to draw the three-dimensional structure of a small organic molecule.
With simple software controls, the molecule could be rotated in space and redisplayed. Similarly, the conformation of the molecule could be changed by rotating one portion of the molecule around a bond that formed an isthmus between it and the remainder of the molecule. The display of the molecule was done in pairs of unages where the unage of one molecule was rotated 5 degrees around the vertical axis.
This pro- duced a stereoscopic effect that permitted the three-dimensional structure of the molecule to be perceived without having to rotate it continually. All of molecular graphics has simply been an exten- sion and refinement of these powerful ideas.
The number of line segments drawn per second has risen dramatically. Color has been added. Hardware stereo devices have been developed, and very recently powerful array processors have been added to permit the rapid calculation of molecular energetics during modeling.
These techniques for display and modeling were developed and refined in a few academic research laboratories. They began to diEuse to biochemical and genetics laboratories in academic and industrial institutions worldwide. Over the past 20 years, the manufacturers of computer and graphics hardware have begun to recognize that molecular graphics and modeling is a substantial market.
We are now at the critical point in this respect. Hard- ware manufacturers are now willing to design workstations i. A new class of workstations is expected in the next year. The four functions, molecular energy computation, molecular configuration control, molecular graphics, and reason- ing about molecular structure, will be integrated in one computer system.
Market forces can be expected to expand the number of different machines and the features that each machine offers. Standards at various levels, an defined by the International Standards Organization ISOwill permit ex- isting and new program systems to be transported rapidly onto the PSC class members.
The standardization efforts will permit a decoupling of the computational support systems i. The existence of standards, however, does not guarantee portable program code. Scientists who write new programs must know about these standards and write programs that conform to them. Commercial organizations that take existing scientific pro- grams should shape them towards the standard style because, in the end, the size of the commercial market will depend on the abil- ity of end users to piece together working systems from components made out of various standard programs.
If these standardization efforts succeed, then in the future, the molecular modeling com- munity will be able to routinely make smooth transitions to more powerful computer support systems.
Computer graphics representations offer alternative ways of understanding molecular structure and function. They started as the simplest white line drawings on black screens, then progressed to color images, to solid surfaces, to dot surfaces, and to electro- static surfaces.
Intergraph three-dimensional representations and white light hologram representations have been developed and used for molecular structure problems. Intergraph is composed of approximately 20 individual photographs where vertical strips are selected from each photograph and composed into one image. The composite image is viewed through a linear fresne! The next generation of workstation, the PSC, wiD offer ray-traced im- ages as part of the operating system.
In a ray traced image the reflections on a surface are compared by calculating the trajec- tory of light beams from all possible light sources.
This produces in the extreme the reflections of one object on another. A breakthrough in a field such as plasma physics is necessary to make this a reality. The central bottleneck to progress in protein design is our inability to predict protein tertiary structure from amino acid sequence.
The notion put forth by Anfinsen 25 years ago was that the amino acid sequence alone determines tertiary structure. This notion may be too simplistic, and there may indeed be a higher level code than the Nirenberg nucleic acid to amino acid conversion by the ribosome. Since the Anfinsen conjecture and the experimental detail surrounding it are largely prohibitory in nature, they had the effect of discouraging experunentation in expression and folding of proteins.
Scientists who are concerned with protein expression are content with the Nirenberg code and explain away anomalous results because they see no need for any other effect. Scientists concerned with protein folding cannot ex- plain how proteins fold, but then are discouraged by the Anfinsen conjecture from asking for more information from the geneticists. A theory and experiment linking codon utilization in gene struc- ture with the folding of protein structure would be a major step toward reconciling these views.
We assume that we must know the three-dimensional structure of a macromolecule before we can fully understand its function. The problem is, how do we decode the rules that govern the relationship between structure and function? A subset of this problem will be discussed below: Those in the field believe that medicinal chemistry is pomed to undergo a revolution as dramatic as the events in the s and s that transformed organic chemistry from a descriptive to a predictive science.
Since we are at the beginning of a new age, the many challenges ahead do not diminish the excitement of knowing that the solutions are also on the horizon. In anticipating this revolution, we are presupposing that we can or soon will be able to predict the functions of proteins from their structures. In particular, we would need to be able to pre- dict the ability of a protein to recognize and bind a ligand and to predict the structure of the Optimum ligand.
Beyond that, however, we would need to be able to predict how the protein car- ries out its function and how it recognizes and interacts with other macromolecules to alter its own functions and theirs. Although we have learned much about these topics, there are unanswered questions that we must be able to answer before we will be able to make accurate predictions.
Ligands affect the function and properties of hemoglobin in complex ways. Investigators began to attempt to design ligands based on the three-dimensional structure of a protein as soon as such structures were available. They used the structure of hemoglobin as determined by protein crystallography and constructed a wire mode! The investiga- tors used simple concepts of complementary shapes, electrostatic interactions.
The designed com pounds Figuredesignated compounds do indeed mimic the effect of diphosphoglycerate on the dmsociation of oxygen from hemoglobin.
Subsequent crystallographic work supported the pro- posed binding mode.
Next Generation Delivery System for Proteins and Genes of Therapeutic Purpose: Why and How?
In addition, the relative binding energy of various analogues to a number of different hemoglobins was mea- sured for 29 protein-inhibitor combinations. Statistical analysis revealed a highly significant correlation between the strength of binding and the number of covalent and ionic interactions.
An in- tensive biochemical, physiological, and structural examination of the problem suggested that a ligand that binds between the alpha subunits of oxyhemoglobin might have the desired effect. Since no natural ligand for this site was known, the ligands were designed from the protein structure alone and designated compounds 5 and 6 see Figure Although the proposed binding mode has not been experimentally verified, the designed compounds did pros duce the expected change in function of hemoglobin.
One of the compounds is now in clinical trials for the treatment of sickle cell disease. Thus, using rather primitive tools, the Welicome group was able to predict the effect of a small molecule on the function of a protein. The recent experience of Perutz et al. Perutz and coworkers ex- perimentally demonstrated several of the potential binding sites that a molecule might recognize in hemoglobin.
Specifically, they solved the crystal structure of eight ligand-hemogiobin complexes and showed that there are at least six different positions on the protein at which a ligand night form a tight complex.
See text for details. Three of the molecules bins! Each of the bound ligands changes the structure of the proteins so little that the change is barely detectable, yet some of the ligands increase the gelling concentration, some decrease it, and others do not change it at all. This work makes it clear that even after studying structure and function of hemoglobin for 25 years, an investigator may still be puzzled by the functional con- sequences of the minute structural changes that accompany ligand binding.
The work of Perutz et al. Clofibrate raises the gelling concentration of hemoglobin S. Also, it has been used clinically for other disorders and so is known to be absorbed, metabolized, and nontoxic. Yet it cannot be used to treat sickle cell disease because it is so tightly bound to serum albumin that it is not available to bind to the hemoglobin. The lesson to be drawn from this is that when we design a new drug from theoretical principles, we must somehow incorporate the possible interaction of the proposed ligand with all other macromolecules of the body.
Introduction Over the last few years, numerous therapeutic proteins and peptides have been approved for clinical usage. Till date, more than different therapeutic proteins and genes have been approved by US-FDA for clinical use, and various therapeutic proteins are in the process of development [ 12 ].
It was a landmark discovery in the medical science when insulin was purified from bovine and porcine pancreas and was utilized as a life-saving injection for patients with type I diabetes mellitus T1DM in [ 3 ].
At that time, some issues were associated with this insulin treatment such as availability of animal pancreases especially bovine and porcine pancreases, immunogenicity of animal insulin to some patients, and cost of the protein [ 4 ]. The problem was solved through recombinant DNA technology, which helped in the production of recombinant insulin using E.
Next Generation Delivery System for Proteins and Genes of Therapeutic Purpose: Why and How?
Insulin was the first commercially available recombinant therapeutic protein, approved by the US-FDA inand presently is the most significant treatment for T1DM [ 89 ]. Presently, with the help of biotechnology and recombinant DNA technology, several recombinant therapeutic proteins are being developed and marketed as biopharmaceutical, and the sales value of these recombinant proteins has gained the highest level of market share in pharmaceutical sector [ 1011 ].
With the beginning of recombinant DNA technology, the idea was to use nucleic acids to cure diseased cells, especially in cells where gene is deleted or mutated. After this report, there have been many debates on pros and cons of gene therapy technology [ 13 ]. However, slowly, due to novel advantages of gene therapy, it is entering into the mainstream of treatment. More than gene therapy clinical trials have been completed throughout the world and many are continuing [ 14 ].Biomolecules (Updated)
Therefore, developing efficient gene delivery technology is one of the significant areas for pharmaceutical industry in current era [ 15 ]. Presently, pharmaceutical delivery system PDS or drug delivery system DDT is very important for the pharmaceutical industry. Many pharmacological properties of traditional molecules can be improved with the help of DDS [ 1617 ].
The effectiveness and marketability of the drug molecules depend on the mode of DDS. Pharmaceutical industries are prone to generate new DDS which can impart novel properties to existing as well as newly discovered products.
New DDS will be more efficient and safer compared to the existing one [ 18 ]. It has been noted that market value, competitiveness, and patent life may boost up for an existing drug candidate molecule if we use a new DDS. Therefore, the existing drug candidate molecules may offer a new opportunity to increase the market price and competitiveness in the pharmaceutical market [ 21 ].
Conversely, patent expiry is one of the major alarms for the pharmaceutical industry. A new DDS can provide a new marketability to an existing drug molecule. Therefore, the development of novel delivery systems is at high priority for the pharmaceutical companies to capture global market. Biopharmaceuticals especially therapeutic proteins and gene therapy are one of the fastest growing areas of the pharmaceutical business.
The first generation therapeutic protein based drugs are currently passing through a number of difficulties and needs for improvement. The therapeutic protein delivery system TPDS offers longer circulation time for the therapeutic protein in the patient's body and enhanced pharmacokinetics PK and pharmacodynamics PD properties and is now extremely valuable from the commercial point of view [ 23 ].
One the other hand, the efficient gene delivery system can improve the means for delivering genes during gene therapy and thus can contribute toward more successful clinical outcomes [ 24 ]. In this paper, we have tried to highlight next generation delivery systems and benefits of proteins therapy or gene therapy.
Efforts have been made to summarize general procedures for therapeutic protein or gene delivery system and different next generation delivery systems, namely, liposome, PEGylation, HESylation, and nanoparticle based delivery along with their detailed description.
Why Proteins Therapy or Gene Therapy? Over the last few years, biopharmaceuticals especially therapeutic proteins have received great attention. Among the biopharmaceuticals, therapeutic proteins and genes delivery have gained the maximum percentage of market share [ 25 ].
It has been found that protein therapeutics has some advantages over small-molecule drug molecules, which may be summarized as follows.
This treatment can help us without any gene therapy. It is very difficult to imitate this distinctive possessed function of enzymes by simple chemicals. So, there is very little chance for the hindrance of normal biological processes with the therapeutic proteins that cause unsympathetic effect.