RedStorm Scientific

9/2007 – National Cancer Institute awards RedStorm an SBIR grant

RedStorm Scientific was awarded a Small Business Innovative Research (SBIR) grant by the National Cancer Institute. This grant provides funds to further develop our design platform that allows for the efficient and rational re-engineering of therapeutic proteins for optimized solubility properties.

7/2007 – Fyrestar™ for Windows released.

RedStorm Scientific’s technology platform, Fyrestar™ Version 1.0, has been released for the Windows operating system. Supported systems are Windows XP, 2000 and NT. The Windows version of Fyrestar™ is feature-complete with the Linux version.

Documentation can be found here.

Tutorial can be found here.

6/2007 - Rational Protein Design for Optimized Solubility

A software module to automate the process of optimizing a protein structure (through mutational changes) has been incorporated into the Fyrestar™ software suite. Solubility is essential for absorption and distribution. Whereas the body generates proteins as needed, drugs must circulate for days. The ability to re-engineer therapeutic proteins in a rational and automated manner represents a significant technological advance.

Solubility Screenshot

4/2007 - Peptides that modulate SARS infectivity developed.

Development of antiviral agents depends on the ability to interfere with a critical stage in the life cycle of a virus without affecting host cell functions. The receptor binding domain of the SARS corona virus is considered to be the primary viral component involved in the virus:host cell interaction, and thus represents an excellent candidate for an antiviral target. Using the Fyrestar™ technology, small peptides were designed in silico to bind to the receptor binding domain of the SARS virus (see news entry 12/2006 titled “Antiviral agents directed against the SARS Corona Virus.”). Recent experimental tests demonstrated that first generation peptides were in fact able to inhibit and stimulate viral infectivity rates. In duplicate testing, the first generation inhibitor was found to delay cytopathic effect (CPE). This is the anticipated effect for the pre-incubation protocol. A peptide was also developed that was shown to enhance the virulence of SARS (i.e., a stimulant). The stimulant peptide was observed to be benign to the cells in the absence of viral particles. In the accompanying figure, for CPE score: 1=0% cell death, 2=25% cell death, 3=75% cell death, and 4>90% cell death.

Sars Results

12/2006 - Fyrestar™ for Windows in Beta testing stage.

RedStorm Scientific's technology platform, Fyrestar™, is being ported to both the Windows and Mac OS X operating systems. As of December 2006, a Windows version has made it into beta testing. The Mac OS X version is currently in the pre-alpha stage.

12/2006 - Antiviral agents directed against the SARS Corona Virus.

The development of rational approaches that effectively target and prevent viral infection is a strategic objective of the pharmaceutical industry. Although rational design efforts have met with occasional success, a key shortcoming is the difficulty associated with the dynamic nature of a protein structure. Namely, the viral protein targets (in many cases, envelope proteins) do not behave as the static structures usually used to depict them. This poses an obvious difficulty associated with designing ligands for structurally diverse targets – to result in a high binding affinity, the ligand must be compatible with either a low-energy state of the protein, or with multiple higher-energy states.

Using the Fyrestar™ technology, RedStorm Scientific has 1) identified target sites on the SARS spike protein to block viral entry into the cell, 2) designed conformationally constrained disulfide cross-linked cyclic peptide ligands that are structurally compatible with the target sites, and 3) optimized the peptide sequence to maximize the conformational compatibility between the protein and the peptide.

10/2006 - Temperature Dependence Module Added to Fyrestar™.

Recently, the structural representation of the ensemble by Fyrestar™, in which partially folded states are modeled to possess a “dual character” of native-like and unfolded-like properties, has been confirmed in low temperature experiments that offer unique access to the native state ensemble (see Babu et al, Nat. Struct. Mol. Biol. 2004 11 , 352; and Whitten et al, Biochemistry 2006 45 , 10163). This is important because the ensemble states accessible by low temperature experiments are likely the states nearest in energy to the native state under standard conditions, and, as such, the states most important to function and solution behavior.

A module allowing the simulation of temperature effects on the protein ensemble has now been added to the Fyrestar™ software suite.

9/2006 - Fyrestar™ Now Available for Linux

RedStorm Scientific's technology platform, Fyrestar™, is a proprietary suite of powerful analytical tools that accurately predict the thermodynamic properties and solution behavior of proteins based on a structural-thermodynamic model of the protein ensemble. These structural-thermodynamic tools can then be applied to rational design and optimization protocols.

This version of Fyrestar runs on Linux operating systems and allows for the calculation of the protein ensemble, how the ensemble impacts the solution properties of protein, as well as the effect of various environmental perturbations (e.g., pH) on the protein ensemble.

Documentation can be found here.

Tutorial can be found here.

6/2006 - Therapeutic and diagnostic peptides directed against prion diseases

Prion protein related neurodegenerative disorders (one example is the mad cow disease) are a significant threat to the human populace because they are transmissible, able to traverse species, have hereditary forms, and are currently incurable. Unknown co-factors are thought to mitigate disease transmission and to be a primary determinant of any cross-species infection. In order to design effective therapeutics to prion diseases, it is first neccessary to obtain a mechanistic understanding of the disease pathology as well as to determine the interaction of the prion protein with any disease co-factors.

Using the Fyrestar™ technology, RedStorm Scientific has performed computer simulations on the structure of the human prion protein to identify possible binding sites for the disease co-factors. Next, a class of small peptide ligands were designed in silico to chemically react with a candidate site. NMR-based experiments demonstrate that these peptide ligands do in fact bind to the human prion protein as well as inititiate significant structural changes in the protein. The ligands were also shown by experiment to affect the transition of the prion protein to its disease amyloid state, through both inhibition and by stimulating its formation.

1/2006 - A software tool for optimizing the solubility of therapeutic proteins

The therapeutic value of any protein can be easily compromised by low solubility, which often adversely affects purification, yield, activity, shelf-life, and delivery. Solubility concerns are thus frequent obstacles to the development and subsequent FDA approval of pharmaceutical compounds derived from protein models. These facts make the development of a quantifiable description of protein solubility, as well as a design platform that can be used to rationally and efficiently re-engineer therapeutic proteins with increased solubility, a high priority.

Using the Fyrestar™ technology, RedStorm Scientific has developed a quantifiable model of protein solubility as well as a design strategy for engineering protein therapeutics with optimal solution properties.