Porphyrins as Novel Therapeutics for HIV: Mechanism,Advances,and Challenges

Abstract

Porphyrins, a class of heterocyclic macrocycles, have garnered significant attention for their potential antiviral properties, particularly against human immunodeficiency virus (HIV). This review explores how porphyrins and their derivatives inhibit HIV replication, focusing on their interactions with key viral components, including reverse transcriptase, protease, and integrase. In addition, the review highlights the role of porphyrins in photodynamic therapy (PDT) as a novel approach to targeting HIV-infected cells. Recent studies have demonstrated that metalloporphyrins, in particular, exhibit enhanced antiviral activity due to their unique structural and electronic properties. Despite promising in vitro and preclinical results, challenges such as cytotoxicity, bioavailability, and resistance mechanisms remain unaddressed. This review provides a comprehensive analysis of the current state of research on porphyrins as anti-HIV agents, emphasizing their potential as a therapeutic strategy and identifying key areas for future investigation. The findings underscore the importance of porphyrins in the ongoing search for effective antiviral therapies against HIV.

Keywords

porphyrins HIV metalloporphyrins entry inhibitors

Introduction

HIV stands for Human Immunodeficiency Virus, and an estimated 40.8 million people were living with HIV at the end of 2024, with 6,30,000 people dying from HIV-related causes globally.¹ In addition to devastating the familial, social, and economic lives of individuals, HIV stigma is thought to be a significant barrier to accessing prevention, care, and treatment services.² Antiretroviral therapy (ART) is the only treatment available now to treat HIV, which, if taken daily, can decrease the viral load and keep the immune system healthy.³ However, HIV drug resistance happens due to changes in the genetic structure of HIV that affect the ability of medicines to block the replication of the virus. All antiretroviral drugs, including the newer ones, are at risk of becoming partially or fully inactive due to the emergence of a drug-resistant virus.^4,5 Hence, the emergence of new innovative drugs has become a prerequisite. To overcome the developing resistance to drugs, a new compound, Porphyrins, has shown promising results in blocking HIV replication.

Porphyrin is an 18π aromatic macrocyclic compound with four pyrrole units and four bridging carbon atoms in a planar conformation, without which no life can exist on Earth. The structure of the porphyrins can be found in chlorophylls and hemes.,⁶ as shown in Figure 1. Synthetic porphyrins and metalloporphyrins hold a value of great importance, as biological photophysical and photochemical properties are promising candidates for disease treatment, biological imaging, analytical photocatalytic, molecular photovoltaics, and photodynamic therapy (PDT).^7–10 The promising therapeutic approach of PDT relies on the light-induced generation of reactive oxygen species (ROS) by photosensitizing agents.¹¹ It has also shown great potential in cancer.,¹² anti-microbial,¹³ and antiviral therapy.^14,15

FIG. 1.

Structure of Porphyrin and Metalloporphyrin. (a) Porphyrin (b) Metalloporphyrin.

It has not gone unnoticed that resistance to ART has emerged, and we need better compounds to combat it. Recognizing the capabilities of porphyrins in present-day approaches and their future potential, this review discusses their role in HIV research and therapy, including their antiviral activity, and identifies significant gaps requiring urgent attention.

Chemistry and Properties of Porphyrins

Porphyrins are a unique class of compounds that are widely available in nature. They have distinctive photo-physical properties and are highly stable, with a broad absorption profile spanning the ultraviolet (UV) to near-infrared regions.¹⁵ Their excitation promotes an electron to an excited state, followed by either fluorescence or phosphorescence or intersystem crossing to an excited triplet state.¹⁶ The ability of porphyrins to emit fluorescence enables their use as diagnostic tools and is essential for fluorescence-guided tumor dissections and imaging. Their ability to undergo intersystem crossing into an excited triplet state (which produces singlet oxygen) allows their use in therapeutic applications.¹⁴

Most porphyrins and their derivatives are dark purple in color. Water-soluble porphyrins dissolve in water and water-DMF mixtures, whereas water-insoluble porphyrins are soluble in benzene, chloroform, ethanol, and dimethylsulfoxide.¹⁶ Conformational changes in protein structure are induced by porphyrins in the dark as well as under UV light, resulting in reduced enzyme activity and increased proteolytic susceptibility.¹⁷ Photodynamic treatment (PDT) is a clinically approved, non-invasive therapeutic method that targets abnormalities.¹⁸ For instance, in cPDT (anti-cancer PDT), the photodynamic effect acts by generating ROS via a type-I (electron-transfer) or type-II (energy-transfer) mechanism, which disrupts gp120-mediated viral entry and viral replication. Factors affecting photodynamic inactivation (PDI) include net charge, structural features of the PSs (Photosensitizers), irradiation wavelength, effective uptake of PS, and availability of molecular oxygen.¹¹ One of the major advantages of antimicrobial photodynamic therapy (aPDT) and PDI lies in their receptor-independent mechanism of action, where ROS induces multi-target oxidative damage to microbial membranes, proteins, and nucleic acids. This non-specific mode of action prevents microorganisms, including viruses, from developing resistance mechanisms commonly observed with conventional antimicrobial agents.¹⁹

Mechanism of Action of Porphyrin to HIV

The primary mechanism of action of porphyrins against HIV is by binding to the V3 loop of gp120.^20,21 Whereas some porphyrins and metalloporphyrins inhibit the activity of viral enzymes, reverse transcriptase (RT) and protease (PR).^22,23 The reported anti-mechanism of porphyrins differs because their activity is governed by a combination of molecular properties, environmental conditions, and biological accessibility of targets. The main reason is the structure. The charge, the substituent, and planarity govern porphyrin interaction with other molecules. Even though they have the same core, the anionic and cationic porphyrins behave as different drugs. The HIV virion contains three enzymes: RT (RNA-dependent DNA polymerase), which is involved in the synthesis of viral DNA from an RNA template; an integrase that catalyzes the integration of the newly synthesized viral DNA into the host cell’s chromosome; and a PR that cleaves the polyproteins into structural proteins. The stages of transcription and replication of viral RNA/DNA are impossible without the participation of these enzymes, which are targets of chemotherapeutic agents used to treat AIDS.²⁴ The mechanism of action of porphyrins against HIV can be divided into two subgroups based on their core molecular structures.

Anti-HIV mechanism free-base porphyrins

Metal-free porphyrins exhibit anti-HIV activity mainly by viral entry inhibition and nucleic acid interactions. An important determinant involves the attachment of different derivatives to the free-base porphyrin ligands, which governs their interactions with cell receptors and determines their distinct structure-activity relationships. The HIV envelope contains glycoprotein gp120, which contains five variable regions (V1–V5) and five conserved regions (C1–C5).²⁵ The region involved in coreceptor linking is identified as a polycation, including the V3 loop of the gp120 protein and conserved elements adjacent to it.²⁶ To target the V3 loop, porphyrins and their analogues must be negatively charged.²⁶ Porphyrins with anionic groups, such as carboxyl and sulfonate, readily interact with the positively charged and hydrophobic gp-120 V3 loop, thereby preventing its binding with CD4 cell receptors.^27,28 Porphyrins can generate ROS under light exposure (PDT), damaging viral components and infected cells,²⁹ which are not prominent in physiological conditions. Nevertheless, porphyrin binding and antiviral activity may vary across HIV clades due to differences in the V3 loop sequence, charge distribution, and structural accessibility.³⁰ We know that V3 loop composition determines viral tropism (CCR5 vs. CXCR4) through specific amino acid changes, so alteration in this region can markedly impact electrostatic interactions with anionic porphyrins, resulting in strain-dependent differences in antiviral effectiveness.³¹ Recently, it has been reported that carboxyphenyl–hydroxyphenyl-substituted porphyrins, particularly c-PB₂(OH)₂ and PB(OH)₃, have the potential to block viral entry and exhibit significantly enhanced antiviral efficiency upon photodynamic activation. Mechanistic studies concluded that these compounds interact less with host cell CD4 receptors or co-receptors, suggesting that their primary targets are viral envelope components. These porphyrins play a key role as post-attachment entry inhibitors, effectively lowering the infecting potential of newly formed virus, making them photodynamically enhanced antiviral agents.¹⁸ Similarly, sulfonated anionic porphyrins have been reported to attach HIV-1 gp120, particularly within the V3 and C5 domains, and upon photodynamic activation, induce localized oxidative damage that damages envelope protein integrity, therefore resisting viral entry and reducing infectivity without direct involvement of host cell receptors.²¹

Another mechanism of action of porphyrins is intercalation into viral DNA or RNA, disrupting viral replication and transcription.³² Porphyrins and their analogues can form various types of complexes with DNA: intercalates (internal complexes), bind to the minor groove of DNA, bind to the major groove of DNA, and external binding with self-stacking along the DNA surface.²⁴ Tetracationic porphyrins have a great potential for strong electrostatic interactions with DNA through groove binding and partial intercalation, followed by attraction to the negatively charged phosphate backbone. Upon photodynamic activation, these DNA-bound porphyrins generate ROS that trigger oxidative base modifications and strand cleavage, resulting in severe disruption of nucleic acid integrity. This localized ROS-mediated nucleic acid damage represents an important mechanism highlighting porphyrin-based PDI of viruses, specifically those with exposed or weakly protected genomes.³³ This existing literature can be a valuable input for selecting new photochemical methods in photo-biochemistry and photomedicine. Although research on the exact mechanism of action followed by porphyrins in HIV remains unexplored. Evidence indicates that porphyrins may enhance immune responses by modulating cytokine production or activating immune cells.³⁴ Mechanistically, porphyrin-mediated photodynamic activation generates ROS, which can induce immunogenic cell death. This process is characterized by the release of damage-associated molecular patterns, including calreticulin exposure, Adenosine Triphosphate (ATP) release, and High Mobility Group Box 1 (HMGB1) secretion, which promote dendritic cell maturation and antigen presentation.³⁵ These events may subsequently enhance T cell activation and support immune response. However, clear evidence for porphyrin-induced HIV-specific responses—such as cytotoxic T lymphocyte activity or latent reservoir reduction has not been found. Therefore, their immune effect on HIV is not yet proven, showing a gap between theory and actual evidence.

Anti-HIV activity of metalloporphyrins

Metalloporphyrins are compounds with a central metal ion coordinated to a porphyrin ligand that demonstrate enhanced and often broader anti-HIV activity compared to free-base analogues. Previous studies on porphyrins and their analogues have shown that metalloporphyrin complexes often exhibit enhanced binding to various viral targets (e.g., enzymes or envelope proteins), implicating the importance of metal ions in improved antiviral mechanisms.³⁶ A study conducted at the University of Hong Kong (2004) showed that gold (III) porphyrins inhibited HIV-1 reverse transcription. They mixed RT with two building blocks to synthesize DNA- one was labeled with a marker (digoxigenin) and the other with biotin to help it attach later. Once the DNA was made, it was captured in a well coated with streptavidin, which bound to the biotin on the DNA. The marker in the DNA was detected using a light-producing reaction, and this provides the quantification of DNA and at what percentage the gold porphyrins could block the RT enzyme.³⁷

Metallo-tetraphenyl porphyrin tetrasulfonate and its copper derivatives (Metallo-TPPS4 and TPPS4-Cu), sulfonated tetranaphthyl porphyrin (TNapPS), sulfonated tetra-anthracenyl porphyrin (TAnthPS), meso-tetraphenyl sulfonated porphyrins, meso-tetra(4-carboxyphenyl) porphine, and many others display promising potential in in-vitro antiviral activity.²⁴ Likewise, certain metalloporphyrin with Zn(II), Au (III), and V(IV) effectively inhibit HIV RT.^20,27,28,38 The water-soluble oxovanadium(IV) tetraarylporphyrin has demonstrated excellent solution stability against glutathione reduction and high potency (5 µM, 97% inhibition) in inhibiting HIV-1 replication in Hut/CCR5 cells.²³ Oxovanadium(IV) porphyrins stabilize the vanadium ion in physiological conditions and exhibit strong antiviral activity by inhibiting HIV-1 RT, reducing viral replication in infected T-cells. In addition, molecular modeling suggests these metalloporphyrins preferentially bind to the CD4 receptor, thereby blocking viral entry into host cells. Together, they act through a dual mechanism: RT enzyme inhibition and prevention of virus–host cell fusion/entry.³⁹

The photo-inactivation of HIV-1 clinical variants, resistant variants, and HIV-2 variants by the porphyrins has also been reported.³⁷ Similarly, the cationic porphyrins led to the inhibition of de novo virus infection, and the Zn (II)-complexes of T2(OH)2M (A2B2-type) and T(OH)3M (AB3-type) displayed potent inhibition of HIV-1 entry, with T2(OH)2MZn displaying maximal anti-HIV activity.⁴¹ Researchers synthesized a series of meso-substituted porphyrins and assessed their anti-HIV-1 activity under non-photodynamic (non-PDT) and photodynamic (PDT) conditions.

One in vivo study shows the self-transportation and self-modification of porphyrins in anti-tumor studies.⁴² In vivo studies on porphyrins are available in the literature, but the same has not yet been done for HIV.⁴³ A study evaluated various potential natural and synthetic porphyrins for anti-HIV activity. Sulfonated tetra-aryl porphyrins, such as TNapPS and sulfonated tetra-anthracenyl porphyrin (TAnthPS), demonstrated significant inhibition of HIV-1 infectivity by 99% and 96%, respectively. The mechanism involved the inhibition of HIV-1 envelope protein gp120 binding to the CD4 receptor, preventing viral entry into host cells,²⁰ as illustrated in Figure 2.

FIG. 2.

Mechanism of action of Porphyrins.

Clinical Evidence of Porphyrins

Many porphyrin-based compounds are approved by the FDA (U.S. Food and Drug Administration) for medical use, especially PDT. Photofrin showed efficiency in reducing tumor size and improving early and advanced-stage cancer survival outcomes. Visudyne is a second-generation photosensitizer proven to prevent vision loss in patients with wet AMD (age-related macular degeneration).⁴⁴ Another one is Ameluz, which is used in the form of ointment and has been approved in the treatment of actinic keratosis on the face and scalp and has been shown to achieve high clearance rates for superficial actinic keratosis in the phase III clinical trial.⁴⁵ Various porphyrin-based compounds are under clinical trials for their oncology, antimicrobial PDT, and neurological applications. But till now, porphyrins have not been approved as an anti-HIV drug. Many studies have shown porphyrins as a potent entry inhibitor, but these have not made their way to clinical trials yet.^18,41 Clinically approved entry inhibitors like Maraviroc⁴⁶ and Enfuvirtide⁴⁷ act by selectively blocking the CCR5 Coreceptor and inhibiting gp41-mediated membrane fusion, respectively, providing a highly specific mechanism of action. In contrast, the RT, such as⁴⁸ Zidovudine, terminates the DNA synthesis. Whereas porphyrins have a pleotropic mechanism of action, which can reduce the likelihood of resistance, but at the cost of lower specificity and context-dependent efficacy compared to conventional antiretrovirals. Thus, although porphyrins offer mechanistic diversity, current evidence suggests that they do not yet match the potency, selectivity, or clinical reliability of existing entry or RT inhibitors. Their potential may instead lie in adjunctive or niche applications, such as localized antiviral strategies or photodynamic viral inactivation, rather than as direct replacements for standard ART.

Challenges and Future Directions in Porphrin-Based HIV Therapies

Porphyrins and their derivatives have attracted significant interest in HIV therapy due to their unique chemical properties, ability to interact with biomolecules, photodynamic activity, and potential to inhibit viral enzymes. However, several challenges, such as selectivity and toxicity, resistance development, PDT limitations, regulations, and clinical hurdles, hinder the growth of porphyrin-based HIV therapies.

Porphyrins are often used in PDT, requiring light activation to generate ROS. However, this can cause phototoxicity in healthy tissues. The use of porphyrins in PDT for HIV has shown promise but is limited by off-target effects. One study explores how a structural isomer of porphyrin can cause oxidative damage to mitochondria, leading to apoptosis in both targeted and non-targeted cells.⁴⁸ If a porphyrin-based compound causes mitochondrial damage and apoptosis in the dark, it may destroy healthy cells throughout the body rather than only the intended targets. This non-specific toxicity is a “barrier” because it can lead to severe side effects, making the treatment unsafe for human use. The dual role of porphyrins in generating ROS for therapeutic purposes and their potential to cause oxidative damage to healthy tissues has also been reviewed.⁴⁹ Another challenge in this field is latency. HIV reservoirs, such as latent cells in the central nervous system and lymphoid tissues, are challenging to target with porphyrins.⁵⁰ A major limitation is the requirement for controlled light activation, as effective light penetration into deep tissues is limited, restricting PDT primarily to accessible or superficial sites. From a practical perspective, PDT can be suitable for localized infections, such as topical treatment of mucosal transmission sites and disinfection of blood products.⁵¹

HIV has a high mutation rate (approximately 1 mutation per 10,000 bases per replication cycle), which facilitates the rapid emergence of drug resistance.⁵³ Despite the conservation of gp120 being required for receptor interaction, the V3 loop shows variability among HIV-1 clades, with differences in charge, glycosylation, and sequence.⁵³ Particularly, mutations in the V3 loop, as discussed earlier in the anti-HIV mechanism of free-base porphyrins, can alter binding interfaces or reduce accessibility through conformational masking and glycan shielding, thereby diminishing inhibitor efficacy.⁵² Direct experimental evidence for porphyrin base resistance is limited, but these well-established mechanisms of escape observed for other entry inhibitors suggest that resistance to porphyrin-based inhibition is mechanistically plausible.

Another challenge with porphyrin is the delivery and bioavailability. They often have poor solubility, which can limit their effectiveness in vivo. Like porphyrins, fullerenes (the earliest carbon-based nanostructures) have been researched as potential antiviral treatments since their discovery in the mid-1980s. One application commonly associated with this material is antiviral treatment for HIV.⁴⁸ Fullerenes are a perfect fit for nanoparticle-based drug delivery, and diamido diacid diphenyl fulleroid is a synthesized material used for this exact purpose. So, developing effective delivery systems (e.g., nanoparticles and liposomes) is critical for increasing porphyrin solubility and efficacy.

Many antiviral porphyrins fail in vivo because they cannot cross the blood-brain barrier (BBB). This limits the treatment to HIV-associated neurocognitive disorder.⁵⁵ Porphyrins are large and charged molecules, and the BBB only allows small, lipophilic molecules. Another challenge is porphyrins often exhibit poor aqueous solubility and a tendency to aggregate via π–π stacking, resulting in reduced bioavailability and non-specific biodistribution.⁵⁶ These physicochemical limitations significantly impair their absorption and systemic delivery.⁵⁷ Following systemic administration, porphyrins exhibit significant plasma protein binding, which influences their biodistribution and reduces the fraction of free drug available for antiviral activity. This often results in non-specific tissue accumulation rather than selective targeting of infected cells.⁵⁸ Effective HIV therapy requires drug delivery to lymphoid reservoirs; however, the ability of porphyrins to accumulate in these compartments remains poorly characterized. Emerging delivery platforms suggest that targeted systems may enhance lymphatic distribution, although this remains an area requiring further validation.⁵⁹

Treatments based on porphyrins offer a flexible and promising strategy for battling HIV. Their exceptional properties support their use as PDT photosensitizers, drug delivery systems, and antiviral agents. Recent developments in targeted delivery systems, such as nanoparticle-based carriers and ligand-directed porphyrins, hold promise for selectivity and reduced off-target effects. However, substantial optimization and rigorous clinical validation are still required. Even while there are still obstacles to overcome, exploring research will provide insights to answer questions and significantly enhance HIV therapeutics for a cure.

Authors’ Contributions

V.L.J. wrote, revised, and edited. R.G. designed and supervised. S.B. helped with the figures. A.D. revised and edited.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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