Small-molecule regulators that mimic transcription factors

Abstract

Transcription factors (TFs) are responsible for decoding and expressing the information stored in the genome, which dictates cellular function. Creating artificial transcription factors (ATFs) that mimic endogenous TFs is a major goal at the interface of biology, chemistry, and molecular medicine. Such molecular tools will be essential for deciphering and manipulating transcriptional networks that lead to particular cellular states. In this minireview, the framework for the design of functional ATFs is presented and current challenges in the successful implementation of ATFs are discussed.

Figure 1. Transcription activation by transcription factors

TFs are minimally composed of a DNA binding domain (DBD) and an activator domain (AD). The DBD recognize and binds to a DNA sequence to activate the targeted gene(s). The AD recruits the transcriptional machinery components through interactions with RNA polymerase II (RNApol), general transcription factors, (GTFs), (TBP)-associated factors (TAFs), the Mediator complex, chromatin remodeling complexes such as SAGA and Swi/Snf complexes and/or the 19S and 26S components of the proteasome.

Figure 2. DNA binding domains commonly used in ATFs

Zinc fingers (ZF) recognize and bind to 3bp (N1-3) in dsDNA; triplex forming oligonucleotides (TFOs); hairpin polyamides (PAs).

Figure 3. Activation domains commonly used in ATFs

Peptides: amphipathic helix (AH) [62], VP16 from herpes simples virus [112], and P201 [68]. Peptoid [73]. RNA [75] Smallmolecule: isoxazolidine [78] and wrenchnolol [82].

Figure 4. Model of ATF blinking

In the blinking model, the ATF is in rapid equilibrium between an ‘off’ (masked) state and an ‘on’ (exposed). The interconversion between these two states is mediated by intermolecular interactions between the DBD and the AD. In the ‘off’ state, the ATF is masked from the cellular milieu that could lead to degradation; whereas in the ‘on’ state the AD is transiently exposed and is able to recruit the transcriptional machinery.