Nucleotides and nucleic acids bind to the active sites of proteins as part of normal cellular processes in order to regulate biological functions. Proteins can bind either directly to nucleic acids or indirectly through an alternative nucleic acid-protein complex. Modulating these interactions through agonismand antagonism affords potentially broad therapeutic potential and provides an opportunity to target proteins and their biological functions that are typically considered challenging with current modalities.
We design our SMNH compounds to modulate the interaction between nucleotides or nucleic acids and proteins. Because SMNH compounds resemble naturally occurring nucleotides and nucleic acids in the body, we believe they can be more efficient in modulating the interactions with proteins through higher selectivity than traditional small molecule approaches.
We have focused our research on the optimization of SMNH compounds with favorable drug attributes using various approaches including rational drug design, combinatorial chemistry, structural biology and phenotypic screening approaches. By making specific structural modifications to SMNH compounds, we enable them to bind to targets in the diseased tissues with high affinity and selectivity.
Unlike other nucleic acid-based approaches, such as RNA interference, that act by inhibiting specific protein expression through down regulation of messenger RNA, SMNH compounds act directly on proteins and therefore can be used to either upregulate or downregulate the activities of the proteins that play a role in disease processes. For example, we have designed SB 9200 to bindselectively to and upregulate RIG-I and NOD2, each of which is involved in the activation of the body’s immune response to foreign pathogens.
SB 9200 then initiates dual anti-viral mechanisms:
- Inhibits viral replication: SB 9200 binding with RIG-I prevents viral polymerase from engaging viral RNA for replication
- Promotes viral clearance: Activated RIG-I induces endogenous IFN production
The mechanisms by which this happens are depicted in the figures below:
Some of the features of our SMNH compounds that we believe to be important include:
Novel mechanisms of action
SB 9200 and our other SMNH compounds are designed to inhibit viral replication through interaction with polymerase, an enzyme that is implicated in viral replication, and stimulate the innate immune response through the production of natural immunomodulatory cytokines, including interferon, inside cells through the activation of RIG-I and NOD2. We believe that induction of the innate immune response is required for loss or clearance of HBsAg and the achievement of a functional cure.
Multiple routes of delivery, including oral administration
Because our SMNH compounds have small molecule characteristics, they can be delivered orally. Additionally, our SMNH compounds potentially may be delivered intravenously and through intra-nasal and inhalation delivery depending on the target disease.
Treat a broad range of viral, inflammatory and oncological diseases
We design our SMNH compounds to selectively target certain proteins whose presence or activity contributes to disease severity or causes the underlying disease. We believe that this approach is potentially applicable to a broad range of viral, inflammatory and oncological diseases.
No observed immune overstimulation
To date, our SMNH compounds, including SB 9200, have not triggered a nonspecific immune response in our preclinical studies. In addition, no nonspecific immune response was observed in our completed Phase 1 clinical trial of SB 9200.
Potential for use in combination with other antiviral agents
Because our SMNH compounds are designed to act by an immunomodulatory function, we believe they may be developed for use in combination with other antiviral agents that act against viral disease by different mechanisms of action.
Intact excretion limits likelihood of unwanted drug-drug interactions
We believe that SMNH compounds are less likely to have drug-drug interactions with drugs metabolized by CYP450, a major pathway for drug metabolism in the liver, because our SMNH compounds are not metabolized by enzyme systems in the liver and are excreted mostly intact.
Relative ease of manufacturing
Because our SMNH compounds are chemically synthesized by a proprietary solution-phase method, they can be produced in a scalable and reproducible manner.