Do we know what viruses it has activity against?
Good question. I don't know. Identification of those viruses whose replication may be affected by diphenhydramine is not a simple matter. Not only the type of virus, but the stage of infection, would be factors. Way above my pay grade.
The peer reviewed study on the diphenhydramine and lactoferrin combo, captioned "
Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells", was in the context of covid-19. SARS-CoV-2 is an RNA virus. The study discusses viral replication as affected by diphenhydramine interacting with specific parts of sigma receptors in cells.
https://pubmed.ncbi.nlm.nih.gov/23536676/
As stated in that study:
"The antihistamine diphenhydramine, with on-target binding to the Histamine-1 receptor, has known off-target effects at the sigma-1 receptor [
27]. Diphenhydramine was recently shown to inhibit SARS-CoV-2 infectivity and the calculated EC50 for SARS-CoV-2 by plaque reduction assay was 17.4 μg/mL (59.6 μM). This drug is safe, well-characterized, and widely available and so highly relevant in the search for COVID therapeutics. We investigated the ability of diphenhydramine to inhibit SARS-CoV-2 induced cytotoxicity and found an EC50 of 122.0 μg/mL (418 μM;
Figure 8A,B), about 7 times higher than that found in the plaque reduction assay, similar to our findings with AZ66.
We hypothesized that diphenhydramine could be combined with structurally distinct antiviral agents (binding other receptors, not sigma) to reduce its EC50 for antiviral activity against SARS-CoV-2.
In our investigations into sigma-binding ligands, including diphenhydramine, we sought to reduce the EC50 by addition of another safe, and well characterized protein from milk, lactoferrin. The host-iron sequestration protein lactoferrin was reported to exhibit direct antiviral activity against SARS-CoV-2 [28,29], is broadly antimicrobial, and possesses host immunostimulatory properties. We tested combinations of lactoferrin with diphenhydramine to measure effects on reduction of EC50. Co-administration of 400 μg/mL of lactoferrin with diphenhydramine further reduced SARS-CoV-2 induced cytotoxicity and decreased the EC50 by 55.5% to 54.2 μg/mL (185.7 μM;
Figure 8C,D). The antiviral enhancement effects of lactoferrin are more apparent at lower, therapeutically relevant concentrations of diphenhydramine (
Figure 8E). Inhibition of viral replication was also investigated by qPCR (
Figure 8F). Lactoferrin (400 μg/mL) was able to decrease N-protein RNA copies by 28.0% 48 h after infection, compared to DMSO alone controls while 40 μg/mL diphenhydramine alone resulted in 32.2% reduction. When combined, they inhibited 99.97% of N-protein RNA copies, a 3-log reduction that was highly significant. These data demonstrate that combinations of two over-the-counter compounds, with well characterized safety profiles, have synergistic effects on inhibition of SARS-CoV-2."
https://www.mdpi.com/2076-0817/10/11/1514/htm
Timing may be a factor. Here is an excerpt from an Abstract "
Sigma-1 receptor regulates early steps of viral RNA replication at the onset of hepatitis C virus infection":
"Hepatitis C virus (HCV) genome replication is thought to occur in a membranous cellular compartment derived from the endoplasmic reticulum (ER). The molecular mechanisms by which these membrane-associated replication complexes are formed during HCV infection are only starting to be unraveled, and both viral and cellular factors contribute to their formation.
In this study, we describe the discovery of nonopioid sigma-1 receptor (S1R) as a cellular factor that mediates the early steps of viral RNA replication. S1R is a cholesterol-binding protein that resides in lipid-rich areas of the ER and in mitochondrion-associated ER membranes (MAMs). Several functions have been ascribed to this ER-resident chaperone, many of which are related to Ca(2+) signaling at the MAMs and lipid storage and trafficking. Downregulation of S1R expression by RNA interference (RNAi) in Huh-7 cells leads to a proportional decrease in susceptibility to HCV infection, as shown by reduced HCV RNA accumulation and intra- and extracellular infectivity in single-cycle infection experiments. Similar RNAi studies in persistently infected cells indicate that S1R expression is not rate limiting for persistent HCV RNA replication, as marked reduction in S1R in these cells does not lead to any decrease in HCV RNA or viral protein expression. However, subgenomic replicon transfection experiments indicate that S1R expression is rate limiting for HCV RNA replication without impairing primary translation.
Overall, our data indicate that the initial steps of HCV infection are regulated by S1R, a key component of MAMs, suggesting that these structures could serve as platforms for initial RNA replication during HCV infection."
https://pubmed.ncbi.nlm.nih.gov/23536676/
