Target HIV-AIDS - Open Source Grant R&D

Overcoming barriers to obtain funding in order to catalyze drug development can be daunting. Grant authoring services can cost up to $20,000 to develop an individual application for NIH funding in the US. And new ideas without prior efficacy trials are often rejected by grant reviewing boards.

As an experiment, a grant application draft is included below to generate discussion, and harness the wisdom of the crowd to improve it's chances for approval. The goal of the application is to solicit funding for HIV/AIDS research. I believe it is a creative approach to advance HIV/AIDS targeting because it incorporates the synergy of:

A) super-computer aided drug design, B) nano-engineered conjugate structures and combination therapies, C) magnifying antigenic effect through dendritic and metabolic catalysts, and D) Web 2.0 crowd source applications.

Suggestions to improve it's chances to garner funding are welcome from the crowd. I am doing this as a social entrepreneur.

Note that funding to carry out this research may be significantly more than the estimate below ($100,000 USD).

http://en.wikipedia.org/wiki/Social_entrepreneurshiplink text

Grant Title – In-Silico HIV Targeting with Web 2.0 Collaboration

Utilizing Super-Computer Aided Drug Design and Crowd Sourcing Applications to Target HIV Infection and Catalyze Clinical Lab Research

Section I. What is your idea?

The Bill and Melinda Gates priority diseases include targets for which many immunological approaches have yielded suboptimal results. A major emerging cause of vaccine failure may not be an inappropriate selection of antigen target, but the fact that the selected target does not elicit the desired neutralizing and cellular responses since it is presented to the immune system improperly.

This project will feature development of novel immuno-conjugates and combination therapies to magnify antigenic effect towards HIV infection. Our approach proposes utilization of super-computer aided drug design of conjugates and combination therapies, and studying dendritic and metabolic catalysts to potentially magnify existing HIV vaccine response. Drug design will feature development of novel combinations with Lewis X, which targets dendritic cells through Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), thereby amplifying vaccine specific immune responses and memory. After novel drug design is completed, Web 2.0 crowd source applications will facilitate virtual sharing of scientific knowledge, enhance collective intelligence for HIV targeting, and catalyze clinical lab research.

We believe this proposal is a creative approach to advance HIV targeting because it incorporates the synergy of A) super-computer aided drug design, B) nano-engineered conjugate structures and combination therapies, C) magnifying antigenic effect through dendritic and metabolic catalysts, and D) Web 2.0 crowd source applications.

Describe the scientific basis for your idea and why you expect it to succeed.

A) Super-computer Aided Drug Design (SCADD) –

Super-computer-assisted drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Our in-silico research will subcontract use of a novel super-computer and also determine: alternative or novel isomers to proposed immuno-conjugates, identify readily scalable compounds, perform toxicology predictions, and discover action mechanisms for drug proposals.

B) Nano-Engineered Conjugate Structures and Combination Therapies:

In 2006, US researchers showed that carbon nanostructures can be coupled to antibodies and could find use in targeted cancer therapies. The researchers utilized a conjugate immunotherapy system using fullerenes; nano-sized carbon spheres otherwise known as buckyballs to create a fullerene-antibody immuno-conjugate. The research led to conclusions that their fullerene-antibody conjugate targeted cells containing the melanoma antigen almost as well as the free antibody. Additionally, it was concluded that water-soluble fullerenes are a potentially good candidate for therapeutics, because their hollow cage structure of 60 atoms of carbon can be used to contain drugs until they reach the targeted cells. Aside from fullerenes, nano-diamond conjugates are an alternative approach that we are considering. Combination therapy refers to the simultaneous administration of two or more medications to treat a single disease. Combination therapy causes significant savings through: lower treatment failure rate, lower case-fatality ratios, slower development of resistance and consequently, less money needed for the development of new drugs. Our approach would utlize SCADD to develop novel nano-engineered conjugates and/or combination therapies that incorporate dendritic and metabolic catalysts referenced below.

C) Dendritic and Metabolic Catalysts -

Sialyl Lewis X (Lewis X) is a tetrasaccharide carbohydrate that is usually attached to O-glycans on the surface of cells. It plays a vital role in inter-cellular recognition processes. Sialyl Lewis X is one of the most important blood group antigens and is displayed on the terminus of glycolipids that are present on the cell surface. Dendritic cells present antigens to the immune system, and the Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4+ T, and may both influence antigenic presentation and interfere with pathogen transfer in breastfed infants. DC-SIGN targeting through a Lewis X component can greatly magnify immune responses. For this reason, Lewis X is being studied for studying HIV infection in computer aided drug design. Other dendritic and metabolic catalysts under consideration for HIV research include - Granulocyte macrophage colony-stimulating factor (GM-CSF), CpG oligodeoxy-nucleotides (CPG-ODN), Epigallocatechin 3-gallate, Pyridoxal Phosophate, (1,3/1,6) Beta Glucan, and Griffithsin.

D) Web 2.0 Applications that feature Crowd Sourcing and Social Networking -

The term Web 2.0 is commonly associated with web applications that facilitate interactive information sharing, interoperability, user-centered design, and collaboration on the World Wide Web. A Web 2.0 site gives its users the free choice to interact or collaborate with each other in a social media dialogue as creators of user-generated content in a virtual community. We believe utilization of Web 2.0 would be novel distribution of in-silico data for HIV research that would normally be proprietary or pre-publication. Since a grant would be funding the research, our primary goals would be to advance knowledge of the scientific community, as opposed to direct monetization of concepts.

**Section II. How will you test it?

Our plan will be carried out in three main stages:**

1) Utilize super-computer aided drug design (SCADD) to develop a novel database of in-silico data supporting isomer-specific nano-engineered immuno-conjugates and/or novel combination therapies with Lewis X to target HIV infection and improve selective targeting of infected cells. Other dendritic and metabolic catalysts will be studied as budget permits.

2) Convert the in-silico data for two distribution formats – hard copy and virtual.

3) Utilize web 2.0 applications (Wikis and Social Networking Platforms) to support the sharing of scientific information, enhance web based collective intelligence, and build relationships to conduct collaborative clinical laboratory research based on SCADD data.

How will the work you describe be performed within the budget (USD$100,000) and time period (one year) allocated for the initial Phase I award?

Budget allocations, and contractual arrangements will be established with partners having pre-existing technology and methodology to conduct this research. The precursors to collaborative working agreements have been already established prior to submission of this grant proposal. SCADD will consume about 65% of the allocated money. Creating versions of in-silico data for distribution on web 2.0 applications will consume about 25% of the budget. The rest of the budget will provide for outreach efforts to the scientific community to catalyze collaborative clinical lab R&D to target HIV. When research moves to clinical laboratories, hypothesis testing and challenge models will indicate if proposed conjugate and combinations warrant clinical trials. The follow-up would be seeing if other vaccine studies could benefit from this collaborative approach.

[END of draft grant application]