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Friday, 05/11/2012 5:54:20 AM

Friday, May 11, 2012 5:54:20 AM

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From Dr. Diwan, President NNVC and inventor of the underlying newly patented technology and other NNVC licensed patent applications:

Email, Thursday, May 10, 2012

The critical and important difference from these and many other technologies out there and nanoviricides® is that nanoviricides are not just polymer-based technologies. 

Getting a polymer to bind to a specific site on a virus or a cell is not difficult. It can be accomplished with many polymers. However, most such polymers allow a ligand to be attached only at one or both ends of the polymer chain, resulting in a relatively low ligand density. In contrast, the patent describes novel polymers in which we can attach ligands at every repeat unit. This is a major innovation and has not been accomplished before. Binding to a polymer bearing ligands vs the cell surface receptors is the competition that the antiviral agent must win. The balance is strongly in favor of nanoviricides(r) due to the high ligand density we can theoretically accomplish. 

It is not enough to bind to the virus. Such binding would create what may be termed a "precipitate" that would lead to an immune precipitate if the complement system is properly functioning, and then could get cleared by the immune system if the immune system is properly functioning at full capacity. We know from Virology that viruses are intelligent nanomachines and that they succeed in creating a severe infection in a human host only if they succeed in fighting out the host immune system. Most viruses derail the immune system in some way, and there are many different points where they derail it. 

Most approaches being tried currently are based on rigid polymers. Examples- dendrimers, polylactate/polybutyrate and related polymers. The drugs based on these are essentially rigid particles. So the liganded polymer nanoparticle of such could stops at binding to the virus. It may bind to the more than one virus particles, itself appearing like a marble in the middle. However, their surface of interaction with an individual virus particle is small; it is only a tangential interaction. 

The second and even more important key invention in our polymers is that they do not form fixed, rigid particles. They are "metastable" materials. What this means is that put a nanoviricide in water or aqueous phase (as in bodily fluids) and it would appear with ligands displayed outwards and the lipid chains hidden inside. If you put it in a lipidic environment (fatty/oily environment or organic  solvent), it inverts itself inside out, and throws its lipid feet outside and pulls its water-loving parts inside. This is the key feature that allows for a strong interaction with a lipid surface such as virus. Upon binding to the virus, we believe that this metastability property enables the polymeric micelle to spread itself along the virus surface, becoming so thin that the lipid part of the polymer contacts the lipid coat on the virus. Then a well-known switching process called "lipid-lipd fusion" can take place. Many viruses are susceptible to such attack and would fall apart completely [typically, these are viruses that do not require excessive acidification before dismantling themselves in the natural course of infection]. 

A third feature disclosed in a later international patent application is that our polymeric micelle materials intended as antivirals provide acidic microenvironment, similar to that of endosomes in the cells wherein viruses dismantle themselves. This is why susceptible viruses such as MCMV, Influenza and HIV possibly fall apart on attack by a nanoviricide. 

A fourth feature of nanoviricides technologies is that we DO NOT USE native substances, such as peptides or protein fragments derived from natural ligands. We believe that human system has those natural ligands because they are needed for some communication within the human system. We want to minimize interference to the host. Therefore, we develop chemical mimics of the conserved portion of the human receptor that binds to the virus attachment protein(s). We have also used Fab fragments and antibodies as ligands. The small chemical mimics that we develop have had the advantage of being small and thus allowing loading of a large number of ligands per unit mass of the drug. 

In addition, the small chemical ligands we design and develop are much cheaper to produce than the antibodies, ligands, and peptides such as RANTES-petide fragment that others have employed. 

In a mathematical sense, using an antibody or Fab fragment or a natural ligand peptide as a binding ligand is a zeroeth level approximation to the problem. To improve upon it, we design the kind of small chemicals ligands which could be considered a third or fourth generation ahead of using antibodies or peptide fragments. 

I am not trying to attack other technologies brought up by others. We are aware of many more approaches. However, the level of effectiveness we have achieved in preclinical animal studies is astounding compared to the level of success reported for these other technologies. 

We can let the results speak for themselves. 

There are two antiviral nano-scale approaches advancing in commercialization ahead of NanoViricides, Inc. 

One is Star Pharma which employs a dendrimer-based polymer with naphthalene-disulfonate or Sudan-Black mimic-based ligands for microbicide-like placement in (a) vaginal gels and (b) condom gels so that the gel can act as an antiviral, more specifically, as anti-HIV. I submit that if these polymers were suitable for a direct anti-HIV drug intervention, this public company would have trumpeted and developed them for that application. They are in Phase III as microbicide in vaginal gel application. Similar negatively charged polymers have previously failed in Ph 3 clinical studies as microbicides. We hope Star Pharma fares better. However, it does not make an anti-HIV drug. 

Another is NanoBio, which is developing oily substances modified to bear certain types of ligands for specific attack. This technology helped them develop an anti-herpes labialis cream. It has a similar mechanism of action, but each molecule bears only one ligand to bind to the virus as far as we can assess (on the same basis as we can claim that a nanoviricide has a large number of evenly spaced ligands). The approach is similar to or equivalent to liposomes. The limitations of this approach have become evident from a large number of drugs that have been developed and even commercialized based on this approach (and a far larger number of drugs that have been developed but that have failed to reach commercialization). In fact our original technology, patent issued in 2000, was developed to overcome several of the limitations of liposome technologies. And those old technology materials have been shown to be superior to liposomes. 

With the new technology, we have made our own 2000-era and earlier technologies obsolete, we believe.

Most scientists and researchers have focused on a single issue and developed solutions relevant to that single issue. We were the first since 1991 to develop a Systems Engineering approach to development of medicines. A sub-part of the Systems Engineering for Medicines is called Systems Biology, which came into vogue circa 2005. We take into consideration not only the Systems Biology, but also the physicochemical and pharmaco-chemical aspects, aspects related to engineering and engineering design for scale-up to cGMP production, aspects related to transportation and delivery of the drug through the supply chain to the pharmacist, then to the patient, and then into the patient's bodily system. Many drugs fail as they advance in the discovery and development process because they fail to meet some of these criteria.  We set out  these criteria before synthesizing even one chemical. We can proudly say that every substance that we have made has shown clinical effectiveness in animal models, and most have shown effectiveness far superior to the standard-of-care. Our materials have also been safe to date in a large number of varied types of animal studies. That is the power of our Systems Engineering approach. We were uniquely qualified to employ this approach because I in person have training in Chemical Engineering, Chemistry, Biochemistry, Microbiology, Infectious Diseases, Biopolymers, Hematology, Blood Compatibility, as well as Virology. I do not claim to be an expert in any one of these disciplines; I and our team rely on experts for every step that we take. But there is clearly a multidisciplinary fusion that has been active in out team for as long as we have been working. 

Anil R. Diwan, Ph.D.

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