SERPIN-Derived Small Peptide (SP16) as a Potential Therapeutic Agent against HIV-Induced Inflammatory Molecules and Viral Replication in Cells of the Central Nervous System

Yemmy Soler; Myosotys Rodriguez; Dana Austin; Cyrille Gineste; Cohava Gelber; Nazira El-Hage

doi:10.3390/cells12040632

SERPIN-Derived Small Peptide (SP16) as a Potential Therapeutic Agent against HIV-Induced Inflammatory Molecules and Viral Replication in Cells of the Central Nervous System

Cells. 2023 Feb 15;12(4):632. doi: 10.3390/cells12040632.

Authors

Yemmy Soler^{1

2}, Myosotys Rodriguez¹, Dana Austin³, Cyrille Gineste³, Cohava Gelber³, Nazira El-Hage¹

Affiliations

¹ Department of Immunology and Nanomedicine, Herbert Wertheim College of Medicine, Miami, FL 33199, USA.
² Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.
³ Serpin Pharma, 9501 Discovery Blvd Suite 120, Manassas, VA 20109, USA.

Abstract

Despite the success of combined antiretroviral therapy (cART) increasing the survival rate in human immunodeficiency virus (HIV) patients, low levels of viremia persist in the brain of patients leading to glia (microglia and astrocytes)-induced neuroinflammation and consequently, the reactivation of HIV and neuronal injury. Here, we tested the therapeutic efficacy of a Low-Density Lipoprotein Receptor-Related Protein 1 (LRP-1) agonistic small peptide drug (SP16) in attenuating HIV replication and the secretion of inflammatory molecules in brain reservoirs. SP16 was developed by Serpin Pharma and is derived from the pentapeptide sequence of the serine protease inhibitor alpha-1-antitrypsin (A1AT). The SP16 peptide sequence was subsequently modified to improve the stability, bioavailability, efficacy, and binding to LRP-1; a scavenger regulatory receptor that internalizes ligands to induce anti-viral, anti-inflammatory, and pro-survival signals. Using glial cells infected with HIV, we showed that: (i) SP16 attenuated viral-induced secretion of pro-inflammatory molecules; and (ii) SP16 attenuated viral replication. Using an artificial 3D blood-brain barrier (BBB) system, we showed that: (i) SP16 was transported across the BBB; and (ii) restored the permeability of the BBB compromised by HIV. Mechanistically, we showed that SP16 interaction with LRP-1 and binding lead to: (i) down-regulation in the expression levels of nuclear factor-kappa beta (NF-κB); and (ii) up-regulation in the expression levels of Akt. Using an in vivo mouse model, we showed that SP16 was transported across the BBB after intranasal delivery, while animals infected with EcoHIV undergo a reduction in (i) viral replication and (ii) viral secreted inflammatory molecules, after exposure to SP16 and antiretrovirals. Overall, these studies confirm a therapeutic response of SP16 against HIV-associated inflammatory effects in the brain.

Keywords: blood-brain barrier; intranasal delivery; low-density lipoprotein receptor related-protein 1; serine protease inhibitors; therapeutic efficacy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Central Nervous System
HIV Infections*
HIV-1* / physiology
Humans
Mice
Peptides / pharmacology
Serpins*
Virus Replication

Substances

Serpins
Peptides

Grants and funding

Funding provided by the National Institutes of Health (NIH)-National Institute on Mental Health (NIMH) grant MH118985 awarded to N.E-H was used to cover the costs of some reagents and laboratory plastic disposables used in the study.