In Upstate New York, a small biotech struggles against the
odds to provide an HIV therapeutic solution for long term AIDS survivors. As with many small biotech companies, OyaGen
Inc. is working with limited capital to provide a blueprint for a next generation “Trojan Horse” solution that
battles the invading HIV before it replicates its genetic materials.
The “miracle” here is a protein known at APOBEC3G or
A3G. Naturally expressed in white blood
cells, A3G serves as a sentinel for invading genetic material such as HIV. It does so as an enzyme that produces
mutations in the genetic code of HIV. As
in the Trojan Horse story, HIV strikes at our host defense early upon entry and
again prior to the release of new viral particles. In infected individuals, A3G is inactive. In this sleeping state, HIV enters the cell,
replicates by reverse transcription, integrates into the host cell chromosomes
and uses the viral genetic blueprint to produce new viral genomes and viral
proteins for the assembly of new infectious viral particles.
Among the viral proteins produced is viral infectivity
factor or Vif. The primary function of
Vif is to find and bind to A3G and to trick the cells into destroying the
sentinel as if it were cellular waste.
In the absence of Vif, scientists around the world have shown that A3G
will slip into the viral particle assembly process to become part of newly
formed viruses. A3G is then able to be
delivered into the next cell like the Greeks in the Trojan Horse story that is
infected and strike the virus as it attempts to reverse transcript copies of
its genetic material.
OyaGen, Inc’s founder and CEO, Dr. Harold C. Smith, OyaGen
CEO, is the first to commercially develop therapeutics that target Vif. Smith has identified new chemical scaffolds
that prevent he inhibition of HIV replication by blocking Vif-dependent A3G
degradation. OyaGen has aggressively
pursued “drugging” the Vif pathway by establishing methods that will identify
antagonists of Vif using a total 6 independent drug discovery methods.
Based on Dr. Smith’s early published studies about A3G,
Smith proposed that A3G activation is another key to any strategy involving Vif
antagonists. Compounds that activate A3G
will enable a maximum and preemptive attack on HIV infection. Funded through the Bill and Melinda Gates
Grand Challenges in Exploration mechanism, OyaGen established
the methods to find compounds that liberate A3G from the confining RNA while
preserving the ability of A3G to inhibit viral replication.
OyaGen’s drug discovery program is developing these
compounds and show under laboratory conditions that pre-treating cells actually
prevents infection. When combined with
Vif antagonist, A3G activators have an additive knockdown of HIV infection that
enables lower doses of both treatments to be effective. Activating A3G ensures that each AIDS patient
can capitalize on their natural antiviral potential. Considering that A3G is a human cellular
protein whose mutability is far less likely than that of an HIV protein, the
new strategy of enabling A3G will have positive long term treatment outcomes.
