Friday Hope: TCM: Japanese Honeysuckle: Targeting SARS-CoV-2 PLpro

Inhibiting this protease of SARS-CoV-2 disrupts replication and prevents immune evasion.

As I have stated before, it is important to take whatever safe and effective steps we can during an acute COVID infection to allow our bodies to eradicate the virus and its Spike Protein as quickly as possible. In addition to targeting the Spike Protein directly, targeting other SARS-CoV-2 viral proteins can assist in bringing the infection to an end and keeping our immune systems as active as possible against it.

One protein that caught my attention as a therapeutic target is the papain-like protease (PL^pro). This enzyme performs two major functions during a SARS-CoV-2 infection. It generates non-structural proteins to assist in the viral replicase complex assemble and it cleaves host proteins resulting in interference with immune surveillance.

PLpro is a key enzyme encoded by SARS-CoV-2 that recognizes and cleaves the LXGG consensus sequence (Leu-X-Gly-Gly, X refers to unspecific amino acids) of both viral and host proteins (Klemm et al., 2020). Cleavage of the viral polyprotein at the LXGG site generates non-structural proteins (nsp1–3) to participate in the assembly of the viral replicase complex, which initiates replication and transcription of the viral genome (Hu et al., 2021a). Beyond the ability to process viral proteins, ample evidence indicates that PLpro can also manipulate host proteins to evade antiviral responses. For example, recent studies demonstrated that SARS-CoV-2 PLpro could bind to, interact with and finally cleave the interferon stimulated gene product-15 (ISG15) modifier from melanoma differentiation-associated protein 5 (MDA5) to escape immune surveillance.

Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506144/

Because PL^pro is more conserved than the Spike Protein (it doesn’t mutate as much) it is easier to target. A very promising paper was published this week showing that a compound known as GZNL-P36 was very effective at targeting PL^pro.

The co-crystal structures of PL 26 pro with leads revealed that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor’s potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 μM, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS32 CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro 33 inhibitor is a promising SARS-CoV-2 therapy.

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
https://www.biorxiv.org/content/10.1101/2024.04.03.587743v2.full.pdf

This immediately inspired me to find a natural compound that could achieve the same result. After researching this over the past several days, I discovered that, indeed, nature has provided us with a natural compound that can inhibit PLpro.

May I please introduce you to the TCM herb Lonicera japonica, or Japanese Honeysuckle.

Lonicera japonica, known as Japanese honeysuckle and golden-and-silver honeysuckle, is a species of honeysuckle native to East Asia, including many parts of China. It is often grown as an ornamental plant, but has become an invasive species in a number of countries. Japanese honeysuckle is used in traditional Chinese medicine.

Description

Lonicera japonica is a twining vine able to climb up to 10 m (33 ft) high or more in trees, with opposite, simple oval leaves 3–8 cm (1.2–3.1 in) long and 2–3 cm (0.79–1.18 in) broad. When its stems are young, they are slightly red in color and may be fuzzy. Older stems are brown with peeling bark, and are often hollow on the inside.

The flowers are double-tongued, opening white and fading to yellow, and sweetly vanilla scented. The fruit, which is produced in fall, is a black spherical berry 3–4 mm (0.12–0.16 in) diameter containing a few seeds. While the nectar from the flowers can be safely consumed by humans, all other parts of the plant have the potential to be toxic.

Lonicera japonica
https://en.wikipedia.org/wiki/Lonicera_japonica

This remarkable plant has the ability to perform exactly what GZNL-P36 does: Target the SARS-CoV-2 PLpro.

L. japonica is not only the most prescribed antiviral TCM, but also a food-medicine herb widely used in daily tea drinks, soft drinks and cosmetics (Shang et al., 2011). Notably, abundant studies indicated that L. japonica is effective for coronaviruses. For instance, cytopathic morphology-based assays by Wu et al. (2004). demonstrated that L. japonica extracts had significant antiviral effects against SARS-CoV. Furthermore, the antiviral efficacy of L. japonica was confirmed by accumulating clinical evidence. During the battle against SARS-CoV-2, greater than 85% of COVID-19 patients in China received TCM treatment and clinical results revealed that TCM could significantly alleviate the symptoms of mild patient (Wang et al., 2021; Yang et al., 2020). Among these TCMs, two L. japonica formulas, namely “Lianhua Qingwen capsule” and “Jinhua Qingan granules”, are listed as recommended medicine for COVID-19 treatment in the “Diagnosis and Treatment Scheme for Novel Coronavirus Pneumonia (Trial fourth edition, Fifth edition, Sixth edition, Seventh edition)”, owing to their obvious curative effect (Hu et al., 2021b; Wei, 2020; Zhang et al., 2020). Remarkably, L. japonica acts as the sovereign drug in both formulas, indicating a principal role in their therapeutic effect for COVID-19 treatment. Nonetheless, the active ingredients and the mechanism underlying the antiviral effect of L. japonica against SARS-CoV-2 remains elusive. In this context, it is of great significance to clarify the active ingredients in L. japonica responsible for SARS-CoV-2 inhibition. This study demonstrated for the first time that 9 exhibited potent inhibition of both proteolytic and deISGylation activities of SARS-CoV-2 PLpro. Our findings suggest that 9 might at least in part contribute to the antiviral activity of L. japonica by inhibiting PLpro, which provide useful information to support the clinical treatment of COVID-19 by L . japonica. In addition, considering the wide applications of L. japonica as a food-medicine herb, further studies regarding the in vivo antiviral activity and pharmacokinetic investigation of 9 will be worthwhile.

Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506144/

Here we have yet another gift from nature to help us in our battle against our unnatural foe. We will continue to learn. We will continue to find the chinks in its armor and fight to defeat it.

I wish all a blessed, hopeful and beautiful Spring weekend.