Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window

Abstract

AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators—including prostratin, ingenol esters, bryostatin, and their analogs—are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.

Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation

“…Prostratin is approximately tenfold less potent than bryo-1 as a PKC modulator (Beans et al, 2013;Marsden et al, 2017), while SUW014 has similar PKC binding affinities relative to bryo-1 ( Table 1). The bryolog SUW275 (synthesis described in Sloane et al, 2020) is "capped" by acylation of the pharmacophorically required C26 hydroxyl group near the C-ring, which as expected abrogates binding to PKC (Table 1). Interestingly, the prostratin analog SUW014 similarly replicated bryo-1 actions on mBMDCs, while the PKC non-binding bryolog SUW275 had no effect ( Figure 2C).…”

“…Bryo-1 has anti-tumorigenic properties and has been tested in multiple human clinical trials of solid and hematologic malignancies (Clamp and Jayson, 2002). It is currently under investigation in pre-clinical or clinical studies of Alzheimer's disease (Farlow et al, 2019;clinicaltrials.gov, NCT03560245), HIV latency reversal (Bullen et al, 2014;Gutierrez et al, 2016;Laird et al, 2015;Sloane et al, 2020), and antigenic stimulation to augment CAR-T immunotherapy (Hardman et al, 2020;Ramakrishna et al, 2019).…”

Plant Metabolic Gene Clusters: Evolution, Organization, and Their Applications in Synthetic Biology

“…Casbene-derived metabolites, such as prostratin and ingenol-3,20-dibenzoate (IDB), are known to activate protein kinase C- (PKC-) mediated signaling, which is involved in repolarizing cardiac muscle cells, and could be used for treating cardiovascular disorders (Jiang et al, 2018 ). Prostratin and Ingenol derivatives are known to be potential latency reversal agents (LRA) and are found to clear the latently infected cells of HIV (Sloane et al, 2020 ). In addition, casbene-derived ingenol mebutate upsurges the neutrophil-mediated tumor cell degradation of subcutaneous melanoma (Braun et al, 2018 ).…”

Inconsistent reversal of HIV-1 latency ex vivo by antigens of HIV-1, CMV, and other infectious agents

“…These strategies have so far shown very limited success [ 11 – 14 ]. Agents under investigation as LRAs include various types of protein kinase C (PKC) activators (for example, bryostatin-1), HDAC inhibitors (for example, panobinostat and romidepsin), and BRD4 inhibitors (for example, JQ1), among others [ 15 – 19 ]. Most of these LRAs lack specificity for the cells that contain the viral reservoir.…”